N-biphenylmethyl aminocycloalkanecarboxamide derivatives

ABSTRACT

N-Biphenyl(substituted methyl) aminocycloalkanecarboxamide derivatives are bradykinin B1 antagonists or inverse agonists useful in the treatment or prevention of symptoms such as pain and inflammation associated with the bradykinin B1 pathway.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is the National Stage of International Application No.PCT/US03/05782, filed 4 Feb. 2003 which claims the benefit under 35U.S.C. 119(e) of U.S. Provisional Application Nos. 60/355,062, filed 8Feb. 2002 and 60/410,775 filed 12 Sep. 2002.

BACKGROUND OF THE INVENTION

This invention is directed to aminocycloalkanecarboxamide compounds. Inparticular, this invention is directed to aminocycloalkanecarboxamidecompounds that are bradykinin antagonists or inverse agonists.

Bradykinin (“BK”) is a kinin which plays an important role in thepathophysiological processes accompanying acute and chronic pain andinflammation. Bradykinin (BK), like other kinins, is an autacoid peptideproduced by the catalytic action of kallikrein enzymes on plasma andtissue precursors termed kininogens. The biological actions of BK aremediated by at least two major G-protein-coupled BK receptors termed B1and B2. It is generally believed that B2 receptors, but not B1receptors, are expressed in normal tissues and that inflammation, tissuedamage or bacterial infection can rapidly induce B1 receptor expression.This makes the B1 receptor a particularly attractive drug target. Theputative role of kinins, and specifically BK, in the management of painand inflammation has provided the impetus for developing potent andselective BK antagonists. In recent years, this effort has beenheightened with the expectation that useful therapeutic agents withanalgesic and anti-inflammatory properties would provide relief frommaladies mediated through a BK receptor pathway (see e.g., M. G. Bockand J. Longmore, Current Opinion in Chem. Biol., 4:401–406(2000)).Accordingly, there is a need for novel compounds that are effective inblocking or reversing activation of bradykinin receptors. Such compoundswould be useful in the management of pain and inflammation, as well asin the treatment or prevention of diseases and disorders mediated bybradykinin; further, such compounds are also useful as research tools(in vivo and in vitro).

Canadian Published Application No. 2,050,769 discloses compounds of theformula:

which are intermediates in the preparation of angiotensin IIantagonists.

SUMMARY OF THE INVENTION

The present invention provides biphenyl cycloalkanecarboxamidederivatives which are bradykinin antagonists or inverse agonists,pharmaceutical compositions containing such compounds, and methods ofusing them as therapeutic agents.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides compounds of formula I andpharmaceutically acceptable salts thereof:

wherein

-   R¹ and R² are independently selected from    -   (1) hydrogen and    -   (2) C₁₋₄ alkyl;-   R^(4a) and R^(4b) are independently selected form    -   (1) hydrogen,    -   (2) halogen, and    -   (3) C₁₋₄ alkyl optionally substituted with 1 to 4 groups        selected from halogen, OR^(a), OC(O)R^(a), S(O)_(k)R^(d),        OS(O)₂R^(d), and NR¹R², or R^(4a) and R^(4b) together with the        carbon atom to which they are both attached form an exo-cyclic        methylene optionally substituted with 1 to 2 groups selected        from C₁₋₄ alkyl optionally substituted with 1–5 halogens and        C₁₋₄ alkyloxy;-   R⁵ is selected from    -   (1) C₁₋₆ alkyl optionally substituted with 1 to 5 groups        independently selected from halogen, nitro, cyano, OR^(a),        SR^(a), COR^(a), SO₂R^(d), CO₂R^(a), OC(O)R^(a), NR^(b)R^(c),        NR^(b)C(O)R^(a), NR^(b)C(O)₂R^(a), C(O)NR^(b)R^(c), C₃₋₈        cycloalkyl,    -   (2) C₃₋₈ cycloalkyl optionally substituted with 1 to 5 groups        independently selected from halogen, nitro, cyano and phenyl,    -   (3) C₃₋₆ alkynyl,    -   (4) C₂₋₆ alkenyl optionally substituted with hydroxyethyl,    -   (5) (CH₂)_(k)-aryl optionally substituted with 1 to 3 groups        independently selected from halogen, nitro, cyano, OR^(a),        SR^(a), C(O)₂R^(a), C₁₋₄ alkyl and C₁₋₃ haloalkyl, wherein aryl        is selected from phenyl, 3,4-methylenedioxyphenyl and naphthyl;    -   (6) (CH₂)_(k)-heterocycle optionally substituted with 1 to 3        groups independently selected from halogen, nitro, cyano,        OR^(a), SR^(a), C₁₋₄ alkyl and C₁₋₃ haloalkyl wherein said        heterocycle is selected from (a) a 5-membered heteroaromatic        ring having a ring heteroatom selected from N, O and S, and        optionally having up to 3 additional ring nitrogen atoms wherein        said ring is optionally benzo-fused; (b) a 6-membered        heteroaromatic ring containing from 1 to 3 ring nitrogen atoms        and N-oxides thereof, wherein said ring is optionally        benzo-fused; and (c) a 5- or 6-membered non-aromatic        heterocyclic ring selected from tetrahydrofuranyl,        5-oxo-tetrahydrofuranyl, 2-oxo-2H-pyranyl,        6-oxo-1,6-dihydropyridazinyl,    -   (7) C(O)₂R^(a), and    -   (8) C(O)NR^(b)R^(c);-   R^(6a) is selected from    -   (1) C₁₋₈ alkyl optionally substituted with 1–5 groups        independently selected from halogen, nitro, cyano, COR^(a),        CO₂R^(a), C(O)NR^(b)R^(c), OR^(a), OC(O)R^(a), SR^(a), SO₂R^(d),        S(O)R^(d), NR^(b)R^(c), NR^(b)C(O)R^(a), NR^(b)SO₂R^(d),        NR^(b)CO₂R^(a),    -   (2) C₃₋₈ cycloalkyl,    -   (3) C₂₋₈ alkenyl optionally substituted with CO₂R^(a),    -   (4) halogen,    -   (5) cyano,    -   (6) nitro,    -   (7) NR^(b)R^(c),    -   (8) NR^(b)C(O)R^(a),    -   (9) NR^(b)CO₂R^(a),    -   (10) NR^(b)C(O)NR^(b)R^(c),    -   (11) NR^(b)C(O)NR^(b)CO₂R^(a),    -   (12) NR^(b)SO₂R^(d),    -   (13) CO₂R^(a),    -   (14) COR^(a),    -   (15) C(O)NR^(b)R^(c),    -   (16) C(O)NHOR^(a),    -   (17) C(═NOR^(a))R^(a),    -   (18) C(═NOR^(a))NR^(b)R^(c),    -   (19) OR^(a),    -   (20) OC(O)R^(a),    -   (21) S(O)_(k)R^(d),    -   (22) SO₂NR^(b)R^(c), and    -   (23) optionally substituted heterocycle where the heterocycle is        a 5-membered heteroaromatic ring having a ring heteroatom        selected from N, O and S, and optionally having up to 3        additional ring nitrogen atoms, 4,5-dihydro-oxazolyl and        4,5-dihydro-1,2,4-oxadiazolyl, and wherein said substituent is 1        to 3 groups independently selected from C₁₋₄ alkyl optionally        substituted with 1 to 5 halogen atoms, OR^(a) or OC(O)R^(a),-   R^(6b) and R^(6c) are independently selected from    -   (1) hydrogen, and    -   (2) a group from R^(6a); with the proviso that not more than one        of-   R^(6a), R^(6b), and R^(6c) is a heterocycle;-   R^(7a) and R^(7b) are independently selected from    -   (1) hydrogen,    -   (2) halogen,    -   (3) cyano,    -   (4) nitro,    -   (5) OR^(a),    -   (6) CO₂R^(a),    -   (7) C(O)NR^(b)R^(c),    -   (8) C₁₋₄ alkyl optionally substituted with 1 to 5 halogen atoms,    -   (9) NR^(b)R^(c), and    -   (10) S(O)_(k)R^(d);-   R^(a) is selected from    -   (1) hydrogen,    -   (2) C₁₋₄ alkyl optionally substituted with 1 to 5 halogen atoms,    -   (3) phenyl optionally substituted with 1 to 3 groups        independently selected from halogen, cyano, nitro, OH, C₁₋₄        alkyloxy, C₃₋₆ cycloalkyl and C₁₋₄ alkyl optionally substituted        with 1 to 5 halogen atoms,    -   (4) C₃₋₆ cycloalkyl, and    -   (5) pyridyl optionally substituted with 1 to 3 groups        independently selected from halogen and C₁₋₄ alkyl;-   R^(b) and R^(c) are independently selected from    -   (1) hydrogen,    -   (2) C₁₋₄ alkyl optionally substituted with 1 to 5 groups        independently selected from halogen, amino, mono-C₁₋₄alkylamino,        di-C₁₋₄alkylamino, and SO₂R^(d),    -   (3) (CH₂)_(k)-phenyl optionally substituted with 1 to 3 groups        selected from halogen, cyano, nitro, OH, C₁₋₄ alkyloxy, C₃₋₆        cycloalkyl and C₁₋₄ alkyl optionally substituted with 1 to 5        halogen atoms, and    -   (4) C₃₋₆ cycloalkyl, or-   R^(b) and R^(c) together with the nitrogen atom to which they are    attached form a 4-, 5-, or 6-membered ring optionally containing an    additional heteroatom selected from N, O, and S; or-   R^(b) and R^(c) together with the nitrogen atom to which they are    attached form a cyclic imide;-   R^(d) is selected from    -   (1) C₁₋₄ alkyl optionally substituted with 1 to 5 halogen atoms,    -   (2) C₁₋₄ alkyloxy, and    -   (3) phenyl optionally substituted with 1 to 3 groups selected        from halogen, cyano, nitro, OH, C₁₋₄ alkyloxy, C₃₋₆ cycloalkyl        and C₁₋₄ alkyl optionally substituted with 1 to 5 halogen atoms;-   k is 0, 1 or 2; and-   m is 0 or 1.

For compounds of formula I, examples of R¹ and R² include hydrogen,methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl andsec-butyl. In one embodiment of formula I are compounds wherein R¹ andR² are each hydrogen.

Examples R^(4a) and R^(4b) for compounds of formula I include hydrogen,methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl,t-butyl, chlorine, fluorine, bromine, chloromethyl, 1-chloroethyl,hydroxymethyl, 2-methoxyethyl, ethoxymethyl, acetyloxymethyl,methylthiomethyl, aminomethyl, methylamino-methyl,(dimethylamino)methyl, (methylsulfonyl)oxymethyl, and the like; orR^(4a) and R^(4b) on the same carbon atom taken together representmethylene. In one embodiment of formula I are compounds wherein one ofR^(4a) and R^(4b) is hydrogen and the other is selected from hydrogen,halogen and C₁₋₄ alkyl optionally substituted with a group selected fromhalogen, OR^(a), OC(O)R^(a), S(O)_(k)R^(d), OS(O)₂R^(d), and NR¹R², orR^(4a) and R^(4b) together with the carbon atom to which they are bothattached form an exo-cyclic methylene. In one subset thereof R^(4a) andR^(4b) are each hydrogen; in another subset R^(4a) is hydrogen andR^(4b) is selected from CH₂-halogen, CH₂—OR^(a), CH₂—OC(O)R^(a),CH₂—S(O)_(k)R^(d), CH₂—OS(O)₂R^(d), and CH₂—NR¹R²; in a further subsetR^(4a) is hydrogen and R^(4b) is selected from hydroxymethyl,acetyloxymethyl, chloromethyl, (methanesulfonyl)oxymethyl,(methylthio)methyl and (dimethylamino)methyl.

Examples of R⁵ for compounds of formula I include methyl, ethyl,n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, t-butyl,1-ethylpropyl, 2,2-dimethyl-propyl, bromomethyl, chloromethyl,dichloromethyl, difluoromethyl, trifluoromethyl, chlorodifluoromethyl,cyanomethyl, aminomethyl, acetylaminomethyl, dimethyl-aminomethyl,hydroxymethyl, methoxymethyl, ethoxymethyl, methylsulfonylmethyl,phenylthiomethyl, phenoxymethyl, 1-aminoethyl, 1-acetylaminomethyl,1-imidazolyl-methyl, t-butoxycarbonylaminomethyl,3-pyridylcarbonylmethyl, 1-chloroethyl, 1,1-dichloroethyl,2,2,2-trifluoroethyl, pentafluoroethyl, 2-methoxyethyl, 2-phenylethyl,2-cyclopentylethyl, 2-carboxyethyl, 2-methoxy-2-oxoethyl, 2-nitroethyl,1,1-difluoro-1-hydroxypropyl, 1-hydroxypropyl, 2-oxopropyl,3-methoxy-3-oxopropyl, 1-cyano-cyclopropyl, cyclopropyl, cyclopentyl,2-phenylcyclopropyl, allyl, ethenyl, 1-(1-hydroxyethyl)vinyl, 3-butynyl,propargyl, phenyl, benzyl, 3,5-bis(trifluoromethyl)-phenyl,2,4difluorophenyl, 4-methylphenyl, 3,4dimethoxybenzyl,3,4-dimethoxyphenyl, 4-cyanophenyl, 3-nitrophenyl, 2-naphthyl,3,4-methylenedioxyphenyl, 3-cyanophenyl, 2-cyanophenyl, 3-fluorophenyl,3-methoxyphenyl, 3-chlorophenyl, 3,4-dichlorophenyl,3,5-dimethoxyphenyl, 3-trifluoromethylphenyl, 3-methylphenyl,3,5-dichlorophenyl, 2-hydroxyphenyl, 3-hydroxyphenyl,3-nitro-5-(trifluoromethyl)-phenyl, 5-isoxazolyl, 2-benzothienyl,2-thienylmethyl, 3-pyridyl, 4pyridyl, 2-furyl, 3-furyl, 2-thienyl,3-thienyl, 5-methyl-3-isoxazolyl, 3-tetrahydrofuranyl,4methyl-1,2,5-oxadiazol-3-yl, 5-carboxy-3-pyridyl, 6-hydroxy-2-pyridyl,5-hydroxy-3-pyridyl, 2-hydroxy-3-pyridyl, 2-methyoxy-3-pyridyl,6-chloro-2-pyridyl, 2-chloro-3-pyridyl, 5-chloro-3-pyridyl,5-fluoro-3-pyridyl, 5-bromo-3-pyridyl, 5-methyl-3-pyridyl,3-(trifluoromethyl)-4-pyridyl, 5-(trifluoromethyl)-3-pyridyil,1-methyl-4-pyrazolyl, 1-pyrazolylmethyl, 1-methyl-2-imidazolyl,1,2,4-triazol-1-ylmethyl, 4-thiazolyl, 5-oxo-tetrahydrofuran-2-yl,2-oxo-5-pyranyl, 3-isoxazolyl, 3-pyridazinyl, 5-pyrimidinyl, 4pyrimidinyl, 1-methyl-5-pyrazolyl, 1-methyl-3-pyrazolyl, 5-thiazolyl,5-methyl-1-pyrazolylmethyl, (3-methyl-1,2,4-triazol-5-yl)methyl,2-(1,2,4-triazol-1-yl)ethyl, 5-methyl-4-thiazolyl, 2-quinoxalinyl,methoxycarbonyl, aminocarbonyl, methylaminocarbonyl,dimethylaminocarbonyl, 2-(dimethylamino)ethylaminocarbonyl,benzylaminocarbonyl, 2-phenethylaminocarbonyl.

In one embodiment of formula I are compounds wherein R⁵ is C₁₋₆ alkyloptionally substituted with 1 to 5 groups independently selected fromhalogen, nitro, cyano, OR^(a), SR^(a), COR^(a), SO²R^(d), CO₂R^(a),OC(O)R^(a), NR^(b)R^(c), NR^(b)C(O)R^(a), NR^(b)CO₂R^(a),C(O)NR^(b)R^(c), and C₃₋₈ cycloalkyl. In a one subset thereof arecompounds wherein R⁵ is selected from C₁₋₅ alkyl and C₁₋₃ alkylsubstituted with 1 to 5 groups selected from halogen, nitro, cyano,hydroxy, C₁₋₄ alkoxy, phenoxy, phenylthio, C₁₋₄ alkoxycarbonyl, C₁₋₄alkylsulfonyl, amino, C₁₋₄ alkylamino, di(C₁₋₄ alkyl)amino, C₁₋₄alkylcarbonylamino, C₁₋₄ alkoxycarbonylamino, and C₁₋₄ alkanoyl. In afurther subset R⁵ is selected from C₁₋₃ alkyl substituted with 1 to 5halogen atoms where said halogen is fluoro or chloro.

In another embodiment of formula I are compounds wherein R⁵ is C₃₋₆cycloalkyl optionally substituted with 1 to 3 groups independentlyselected from halogen, nitro, cyano and phenyl. In one subset R⁵ is C₃₋₆cycloalkyl optionally substituted with a group selected from cyano andphenyl.

In another embodiment of formula I are compounds wherein R⁵ is(CH₂)_(k)-aryl optionally substituted with 1 to 3 groups independentlyselected from halogen, nitro, cyano, OR^(a), SR^(a), C₁₋₄ alkyl and C₁₋₃haloalkyl, wherein aryl is selected from phenyl,3,4-methylenedioxyphenyl and naphthyl. In one subset thereof, R⁵ is(CH₂)_(k)-phenyl optionally substituted with 1 to 3 groups independentlyselected from halogen, trifluoromethyl, nitro, cyano, C₁₋₄ alkoxy andC₁₋₄ alkyl; in a further subset R⁵ is phenyl optionally substituted with1 to 2 groups selected from methyl, trifluoromethyl, halogen, cyano,nitro and methoxy.

In another embodiment of formula I are compounds wherein R⁵ is(CH₂)_(k)-heterocycle optionally substituted with 1 to 2 groupsindependently selected from halogen, nitro, cyano, OR^(a), SR^(a), C₁₋₄alkyl and C₁₋₃ haloalkyl wherein said heterocycle is selected fromisoxazolyl, thienyl, pyridinyl, benzothienyl, furyl, tetrahydrofuranyl,oxadiazolyl, 1-oxidopyridinyl, pyrazolyl, imidazolyl, 1,2,4-triazolyl,thiazolyl, 5-oxotetrahydrofuranyl, 2-oxo-2H-pyranyl,6-oxo-1,6-dihydro-pyridazinyl, oxazolyl, pyridazinyl, pyrimidinyl andquinoxalinyl. In one subset thereof R⁵ is selected from isoxazolyloptionally substituted with 1 or 2 C₁₋₄ alkyl, thienyl, pyridinyloptionally substituted with hydroxy, trifluoromethyl or halogen,benzothienyl, furyl, tetrahydrofuranyl, oxadiazolyl optionallysubstituted with C₁₋₄ alkyl, 1-oxidopyridinyl optionally substitutedwith halogen or C₁₋₄ alkyl, pyrazolyl optionally substituted with C₁₋₄alkyl, imidazolyl optionally substituted with C₁₋₄ alkyl,1,2,4-triazolyl optionally substituted with C₁₋₄ alkyl, thiazolyloptionally substituted with C₁₋₄ alkyl, 5-oxotetrahydrofuranyl,2-oxo-2H-pyranyl, 6-oxo-1,6-dihydropyridazinyl, oxazolyl, pyridazinyl,pyrimidinyl and quinoxalinyl. In another subset R⁵ is selected from5-isoxazolyl and 5-pyrimidinyl.

For compounds of formula I examples of R^(6a) include 1-methylethyl,1-hydroxyethyl, methoxymethyl, 2-oxo-2-methoxyethyl, carboxy,methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, phenoxycarbonyl,cyclopentoxycarbonyl, cyclobutoxycarbonyl, cyclopropoxycarbonyl,2,2,2-trifluoroethoxycarbonyl, 4-trifluoromethylphenoxycarbonyl,methoxyaminocarbonyl, methoxycarbonylmethyl, formyl, hydroxy,3-methyl-1,2,4-oxadiazol-5-yl, 5-methyl-1,2,4-oxadiazol-3-yl,1-methyl-5-tetrazolyl, 2-methyl-5-tetrazolyl, cyano, hydroxy, methoxy,difluoromethoxy, trifluoromethoxy, trifluoromethyl, chloro, fluoro,methylaminosulfonyl, dimethylaminosulfonyl, methoxycarbonylamino,ethoxycarbonylamino, 2-fluoroethoxycarbonylamino,isopropoxycarbonylamino, methylaminocarbonylamino, dimethylamino,methylaminocarbonyl, isopropylaminocarbonyl, ethylaminocarbonyl,cyclopropylaminocarbonyl, cyclobutylaminocarbonyl, dimethylaminocarbonyland aminocarbonyl; examples for R^(6b) for compounds of formula Iinclude hydrogen, chloro, fluoro, methyl and methoxycarbonyl; example ofR^(6c) include hydrogen, chloro, fluoro and methyl; and examples ofR^(7a) and R^(7b) include hydrogen, hydroxy, methoxy, methylamino,methylsulfonyl, chloro and fluoro.

In another embodiment of formula I are compounds wherein m is 0.

In another embodiment of formula I are compounds represented by formulaI(1):

wherein m, R¹, R^(4a), R^(4b), R⁵, R^(6a), R^(6b), R^(6c) and R^(7a)have the same definitions as provided under formula I.

In a subset of formula I(1) are compounds wherein R^(6a) is selectedfrom (1) CO₂R^(a), (2) C(O)NHOR^(a), (3) cyano, (4) halogen, (5) OR^(a),(6) C₁₋₈ alkyl optionally substituted with 1–5 halogen atoms, or a groupselected from CO₂R^(a), C(O)NR^(b)R^(c) and OR^(a), (7) C(O)NR^(b)R^(c),(8) NR^(b)C(O)NR^(b)R^(c), (9) NR^(b)C(O)OR^(a), and (10) optionallysubstituted heterocycle where the heterocycle is selected fromoxadiazolyl and tetrazolyl and wherein said substituent is 1 to 3 groupsindependently selected from C₁₋₄ alkyl optionally substituted with 1 to5 halogen atoms, OR^(a) or OC(O)R^(a). In a further subset are compoundswherein R^(6a) is selected from CO₂R^(a), C(O)NHOR^(a),methyltetrazolyl, methyloxadiazolyl, NR^(b)C(O)NR^(b)R^(c), andNR^(b)C(O)OR^(a).

In another subset of formula I(1) are compounds wherein R^(6b) isselected from hydrogen, halogen and CO₂R^(a). In a further subset R^(6b)is hydrogen or halogen.

In another subset of formula I(1) are compounds where R^(6a) is selectedfrom (1) CO₂R^(a), (2) C(O)NHOR^(a), (3) cyano, (4) halogen, (5) OR^(a),(6) C₁₋₈ alkyl optionally substituted with 1–5 halogen atoms, or a groupselected from CO₂R^(a), C(O)NR^(b)R^(c) and OR^(a), (7) C(O)NR^(b)R^(c),(8) NR^(b)C(O)NR^(b)R^(c), (9) NR^(b)C(O)OR^(a), and (10) optionallysubstituted heterocycle where the heterocycle is selected fromoxadiazolyl and tetrazolyl and wherein said substituent is 1 to 3 groupsindependently selected from C₁₋₄ alkyl optionally substituted with 1 to5 halogen atoms, OR^(a) or OC(O)R^(a); R^(6b) is selected from hydrogenand halogen; and R^(6c) is hydrogen.

In another subset of formula I(1) are compounds wherein R⁵ is selectedfrom C₁₋₄ alkyl optionally substituted with 1 to 5 halogen atoms or acyano group, C₃₋₆ cycloalkyl, isoxazolyl, pyrimidinyl and pyridinyl (andN-oxide thereof) optionally substituted with halogen.

In another embodiment of formula I are compounds represented by formulaI(2):

wherein m, R⁵, R^(6a), R^(6b) and R^(7a) have the same definitions asprovided under formula I.

In another embodiment of formula I(2), R^(6b) is hydrogen or halogen. Inone subset R^(6b) is hydrogen; in another subset R^(6b) is fluorine orchlorine.

In another embodiment of formula I(2), R^(6a) is selected from (1)CO₂R^(a), (2) C(O)NHOR^(a), (3) cyano, (4) halogen, (5) OR^(a), (6) C₁₋₈alkyl optionally substituted with 1–5 halogen atoms, or a group selectedfrom CO₂R^(a), C(O)NR^(b)R^(c) and OR^(a), (7) C(O)NR^(b)R^(c), (8)NR^(b)C(O)NR^(b)R^(c), (9) NR^(b)C(O)OR^(a), and (10) optionallysubstituted heterocycle where the heterocycle is selected fromoxadiazolyl and tetrazolyl and wherein said substituent is 1 to 3 groupsindependently selected from C₁₋₄ alkyl optionally substituted with 1 to5 halogen atoms, OR^(a) or OC(O)R^(a). In one subset R^(6a) is selectedfrom CO₂R^(a), C(O)NHOR^(a), methyltetrazolyl, methyloxadiazolyl,NR^(b)C(O)NR^(b)R^(c), and NR^(b)C(O)OR^(a). In a further subset R^(6a)is selected from CO₂R^(a), methyltetrazolyl and methyloxadiazolyl, Inanother embodiment R^(7a) is hydrogen or halogen. In one subset R^(7a)is hydrogen. In another subset R^(7a) is fluorine. In yet another subsetR^(6b) is hydrogen, fluorine or chlorine, and R^(7a) is hydrogen orfluorine.

In another embodiment of formula I(2) R⁵ is selected from C₁₋₄ alkyloptionally substituted with 1 to 5 halogen atoms or a cyano group, C₃₋₆cycloalkyl, isoxazolyl, pyrimidinyl and pyridinyl (and N-oxide thereof)optionally substituted with halogen.

In another embodiment of formula I(2) are compounds wherein m is 0 or 1,R^(6a) is 2-methyl-2H-tetrazol-5-yl, 3-methyl-1,2,4-oxadiazol-5-yl,CO₂R^(a) or C(O)NHOR^(a) wherein R^(a) is C₁₋₄ alkyl, particularlymethyl; R^(6b) is hydrogen, fluorine or chlorine; R⁵ is selected fromC₁₋₄ alkyl optionally substituted with 1 to 5 halogen atoms or a cyanogroup, C₃₋₆ cycloalkyl, isoxazolyl, pyrimidinyl and pyridinyl (andN-oxide thereof) optionally substituted with halogen or trifluoromethyl,particularly trifluoromethyl, difluoromethyl, chlorodifluromethyl,2,2,2-trifluoroethyl, pentafluoromethyl, cyanomethyl, 5-pyrimidinyl,5-isoxazolyl and 5-bromo-3-pyridinyl and N-oxide thereof; and R^(7a) ishydrogen or fluorine.

Unless otherwise stated, the following terms have the meanings indicatedbelow:

“Alkyl” as well as other groups having the prefix “alk” such as, forexample, alkoxy, alkanoyl, alkenyl, alkynyl and the like, means carbonchains which may be linear or branched or combinations thereof. Examplesof alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec-and tert-butyl, pentyl, hexyl, heptyl and the like.

“Alkenyl” means a linear or branched carbon chain containing at leastone C═C bond. Examples of alkenyl include allyl, 2-butenyl, 3-butenyl,1-methyl-2-propenyl, and the like.

“Alkynyl” means a linear or branched carbon chain containing at leastone C≡C bond. Examples of alkynyl include propargyl, 2-butynyl,3-butynyl, 1-methyl-2-propynyl, and the like.

“Cyclic imide” includes succinimide, maleimide, phthalimide and thelike.

“Cycloalkyl” means carbocycles containing no heteroatoms, and includesmono-, bi- and tricyclic saturated carbocycles, as well as fused ringsystems. Such fused ring systems can include one ring that is partiallyor fully unsaturated such as a benzene ring to form fused ring systemssuch as benzofused carbocycles. Cycloalkyl includes such fused ringsystems as spirofused ring systems. Examples of cycloalkyl includecyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, decahydronaphthalene,adamantane, indanyl, indenyl, fluorenyl, 1,2,3,4tetrahydronaphthaleneand the like.

“Haloalkyl” means an alkyl radical as defined above wherein at least oneand up to all of the hydrogen atoms are replaced with a halogen.Examples of such haloalkyl radicals include chloromethyl, 1-bromoethyl,fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl andthe like.

“Halogen” means fluorine, chlorine, bromine and iodine.

“Optionally substituted” is intended to include both substituted andunsubstituted. Thus, for example, optionally substituted aryl couldrepresent a pentafluorophenyl or a phenyl ring.

Optical Isomers—Diastereomers—Geometric Isomers—Tautomers

Compounds described herein may contain an asymmetric center and may thusexist as enantiomers. Where the compounds according to the inventionpossess two or more asymmetric centers, they may additionally exist asdiastereomers.

The present invention includes all such possible stereoisomers assubstantially pure resolved enantiomers, racemic mixtures thereof, aswell as mixtures of diastereomers. The above Formula I is shown withouta definitive stereochemistry at certain positions. The present inventionincludes all stereoisomers of Formula I and pharmaceutically acceptablesalts thereof. Diastereoisomeric pairs of enantiomers may be separatedby, for example, fractional crystallization from a suitable solvent, andthe pair of enantiomers thus obtained may be separated into individualstereoisomers by conventional means, for example by the use of anoptically active acid or base as a resolving agent or on a chiral HPLCcolumn. Further, any enantiomer or diastereomer of a compound of thegeneral Formula I may be obtained by stereospecific synthesis usingoptically pure starting materials or reagents of known configuration.

Some of the compounds described herein contain olefinic double bonds,and unless specified otherwise, are meant to include both E and Zgeometric isomers.

Some of the compounds described herein may exist with different pointsof attachment of hydrogen, referred to as tautomers. Such an example maybe a ketone and its enol form known as keto-enol tautomers. Theindividual tautomers as well as mixture thereof are encompassed withcompounds of Formula I.

Salts

The term “pharmaceutically acceptable salts” refers to salts preparedfrom pharmaceutically acceptable non-toxic bases or acids. When thecompound of the present invention is acidic, its corresponding salt canbe conveniently prepared from pharmaceutically acceptable non-toxicbases, including inorganic bases and organic bases. Salts derived fromsuch inorganic bases include aluminum, ammonium, calcium, copper (ic andous), ferric, ferrous, lithium, magnesium, manganese (ic and ous),potassium, sodium, zinc and the like salts. Preferred are the ammonium,calcium, magnesium, potassium and sodium salts. Salts prepared frompharmaceutically acceptable organic non-toxic bases include salts ofprimary, secondary, and tertiary amines derived from both naturallyoccurring and synthetic sources. Pharmaceutically acceptable organicnon-toxic bases from which salts can be formed include, for example,arginine, betaine, caffeine, choline, N,N′-dibenzylethylenediamine,diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol,ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine,glucamine, glucosamine, histidine, hydrabamine, isopropylamine,dicyclohexylamine, lysine, methylglucamine, morpholine, piperazine,piperidine, polyamine resins, procaine, purines, theobromine,triethylamine, trimethylamine, tripropylamine, tromethamine and thelike.

When the compound of the present invention is basic, its correspondingsalt can be conveniently prepared from pharmaceutically acceptablenon-toxic inorganic and organic acids. Such acids include, for example,acetic, benzenesulfonic, benzoic, camphorsulfonic, citric,ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric,isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic,nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric,p-toluenesulfonic acid and the like. Preferred are citric, hydrobromic,hydrochloric, maleic, phosphoric, sulfuric, and tartaric acids.

Prodrugs

The present invention includes within its scope prodrugs of thecompounds of this invention. In general, such prodrugs will befunctional derivatives of the compounds of this invention which arereadily convertible in vivo into the required compound. Thus, in themethods of treatment of the present invention, the term “administering”shall encompass the treatment of the various conditions described withthe compound specifically disclosed or with a compound which may not bespecifically disclosed, but which converts to the specified compound invivo after administration to the patient. Conventional procedures forthe selection and preparation of suitable prodrug derivatives aredescribed, for example, in “Design of Prodrugs,” ed. H. Bundgaard,Elsevier, 1985. Metabolites of these compounds include active speciesproduced upon introduction of compounds of this invention into thebiological milieu.

Pharmaceutical Compositions

Another aspect of the present invention provides pharmaceuticalcompositions which comprises a compound of Formula I and apharmaceutically acceptable carrier. The term “composition”, as inpharmaceutical composition, is intended to encompass a productcomprising the active ingredient(s), and the inert ingredient(s)(pharmaceutically acceptable excipients) that make up the carrier, aswell as any product which results, directly or indirectly, fromcombination, complexation or aggregation of any two or more of theingredients, or from dissociation of one or more of the ingredients, orfrom other types of reactions or interactions of one or more of theingredients. Accordingly, the pharmaceutical compositions of the presentinvention encompass any composition made by admixing a compound ofFormula I, additional active ingredient(s), and pharmaceuticallyacceptable excipients.

The pharmaceutical compositions of the present invention comprise acompound represented by Formula I (or pharmaceutically acceptable saltsthereof) as an active ingredient, a pharmaceutically acceptable carrierand optionally other therapeutic ingredients or adjuvants. Thecompositions include compositions suitable for oral, rectal, topical,and parenteral (including subcutaneous, intramuscular, and intravenous)administration, although the most suitable route in any given case willdepend on the particular host, and nature and severity of the conditionsfor which the active ingredient is being administered. Thepharmaceutical compositions may be conveniently presented in unit dosageform and prepared by any of the methods well known in the art ofpharmacy.

In practice, the compounds represented by Formula I, or pharmaceuticallyacceptable salts thereof, of this invention can be combined as theactive ingredient in intimate admixture with a pharmaceutical carrieraccording to conventional pharmaceutical compounding techniques. Thecarrier may take a wide variety of forms depending on the form ofpreparation desired for administration, e.g., oral or parenteral(including intravenous). Thus, the pharmaceutical compositions of thepresent invention can be presented as discrete units suitable for oraladministration such as capsules, cachets or tablets each containing apredetermined amount of the active ingredient. Further, the compositionscan be presented as a powder, as granules, as a solution, as asuspension in an aqueous liquid, as a non-aqueous liquid, as anoil-in-water emulsion or as a water-in-oil liquid emulsion. In additionto the common dosage forms set out above, the compound represented byFormula I, or pharmaceutically acceptable salts thereof, may also beadministered by controlled release means and/or delivery devices. Thecompositions may be prepared by any of the methods of pharmacy. Ingeneral, such methods include a step of bringing into association theactive ingredient with the carrier that constitutes one or morenecessary ingredients. In general, the compositions are prepared byuniformly and intimately admixing the active ingredient with liquidcarriers or finely divided solid carriers or both. The product can thenbe conveniently shaped into the desired presentation.

Thus, the pharmaceutical compositions of this invention may include apharmaceutically acceptable carrier and a compound or a pharmaceuticallyacceptable salt of Formula I. The compounds of Formula I, orpharmaceutically acceptable salts thereof, can also be included inpharmaceutical compositions in combination with one or more othertherapeutically active compounds.

The pharmaceutical carrier employed can be, for example, a solid,liquid, or gas. Examples of solid carriers include lactose, terra alba,sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, andstearic acid. Examples of liquid carriers are sugar syrup, peanut oil,olive oil, and water. Examples of gaseous carriers include carbondioxide and nitrogen.

In preparing the compositions for oral dosage form, any convenientpharmaceutical media may be employed. For example, water, glycols, oils,alcohols, flavoring agents, preservatives, coloring agents and the likemay be used to form oral liquid preparations such as suspensions,elixirs and solutions; while carriers such as starches, sugars,microcrystalline cellulose, diluents, granulating agents, lubricants,binders, disintegrating agents, and the like may be used to form oralsolid preparations such as powders, capsules and tablets. Because oftheir ease of administration, tablets and capsules are the preferredoral dosage units whereby solid pharmaceutical carriers are employed.Optionally, tablets may be coated by standard aqueous or nonaqueoustechniques.

A tablet containing the composition of this invention may be prepared bycompression or molding, optionally with one or more accessoryingredients or adjuvants. Compressed tablets may be prepared bycompressing, in a suitable machine, the active ingredient in afree-flowing form such as powder or granules, optionally mixed with abinder, lubricant, inert diluent, surface active or dispersing agent.Molded tablets may be made by molding in a suitable machine, a mixtureof the powdered compound moistened with an inert liquid diluent. Eachtablet preferably contains from about 0.1 mg to about 500 mg of theactive ingredient and each cachet or capsule preferably containing fromabout 0.1 mg to about 500 mg of the active ingredient.

Pharmaceutical compositions of the present invention suitable forparenteral administration may be prepared as solutions or suspensions ofthe active compounds in water. A suitable surfactant can be includedsuch as, for example, hydroxypropylcellulose. Dispersions can also beprepared in glycerol, liquid polyethylene glycols, and mixtures thereofin oils. Further, a preservative can be included to prevent thedetrimental growth of microorganisms.

Pharmaceutical compositions of the present invention suitable forinjectable use include sterile aqueous solutions or dispersions.Furthermore, the compositions can be in the form of sterile powders forthe extemporaneous preparation of such sterile injectable solutions ordispersions. In all cases, the final injectable form must be sterile andmust be effectively fluid for easy syringability. The pharmaceuticalcompositions must be stable under the conditions of manufacture andstorage; thus, preferably should be preserved against the contaminatingaction of microorganisms such as bacteria and fungi. The carrier can bea solvent or dispersion medium containing, for example, water, ethanol,polyol (e.g. glycerol, propylene glycol and liquid polyethylene glycol),vegetable oils, and suitable mixtures thereof.

Pharmaceutical compositions of the present invention can be in a formsuitable for topical use such as, for example, an aerosol, cream,ointment, lotion, dusting powder, or the like. Further, the compositionscan be in a form suitable for use in transdermal devices. Theseformulations may be prepared, utilizing a compound represented byFormula I of this invention, or pharmaceutically acceptable saltsthereof, via conventional processing methods. As an example, a cream orointment is prepared by mixing hydrophilic material and water, togetherwith about 5 wt % to about 10 wt % of the compound, to produce a creamor ointment having a desired consistency.

Pharmaceutical compositions of this invention can be in a form suitablefor rectal administration wherein the carrier is a solid. It ispreferable that the mixture forms unit dose suppositories. Suitablecarriers include cocoa butter and other materials commonly used in theart. The suppositories may be conveniently formed by first admixing thecomposition with the softened or melted carrier(s) followed by chillingand shaping in moulds.

In addition to the aforementioned carrier ingredients, thepharmaceutical formulations described above may include, as appropriate,one or more additional carrier ingredients such as diluents, buffers,flavoring agents, binders, surface-active agents, thickeners,lubricants, preservatives (including anti-oxidants) and the like.Furthermore, other adjuvants can be included to render the formulationisotonic with the blood of the intended recipient. Compositionscontaining a compound described by Formula I, or pharmaceuticallyacceptable salts thereof, may also be prepared in powder or liquidconcentrate form.

The following are examples of representative pharmaceutical dosage formsfor the compounds of Formula I:

Injectable Suspension (I.M.) mg/mL Compound of Formula I 10Methylcellulose 5.0 Tween 80 0.5 Benzyl alcohol 9.0 Benzalkoniumchloride 1.0 Water for injection to a total volume of 1 mL

Tablet mg/tablet Compound of Formula I 25 Microcrystalline Cellulose 415Povidone 14.0 Pregelatinized Starch 43.5 Magnesium Stearate 2.5 500

Capsule mg/capsule Compound of Formula I 25 Lactose Powder 573.5Magnesium Stearate 1.5 600Utilities

Compounds of this invention are antagonists or inverse agonists ofbradykinin receptor, in particular the bradykinin B1 receptor, and assuch are useful in the treatment and prevention of diseases andconditions mediated through the bradykinin receptor pathway such as painand inflammation. The compounds would be effective in the treatment orprevention of pain including, for example, visceral pain (such aspancreatitis, interstitial cystitis, renal colic), neuropathic pain(such as postherpetic neuralgia, nerve injury, the “dynias”, e.g.,vulvodynia, phantom limb pain, root avulsions, painful traumaticmononeuropathy, painful polyneuropathy), central pain syndromes(potentially caused by virtually any lesion at any level of the nervoussystem), and postsurgical pain syndromes (eg, postmastectomy syndrome,postthoracotomy syndrome, stump pain)), bone and joint pain(osteoarthritis), repetitive motion pain, dental pain, cancer pain,myofascial pain (muscular injury, fibromyalgia), perioperative pain(general surgery, gynecological), chronic pain, dysmennorhea, as well aspain associated with angina, and inflammatory pain of varied origins(e.g. osteoarthritis, rheumatoid arthritis, rheumatic disease,tenosynovitis and gout).

Further, the compounds of this invention can also be used to treathyperreactive airways and to treat inflammatory events associated withairways disease e.g. asthma including allergic asthma (atopic ornon-atopic) as well as exercise-induced bronchoconstriction,occupational asthma, viral- or bacterial exacerbation of asthma, othernon-allergic asthmas and “wheezy-infant syndrome”. Compounds of thepresent invention may also be used to treat chronic obstructivepulmonary disease including emphysema, adult respiratory distresssyndrome, bronchitis, pneumonia, allergic rhinitis (seasonal andperennial), and vasomotor rhinitis. They may also be effective againstpneumoconiosis, including aluminosis, anthracosis, asbestosis,chalicosis, ptilosis, siderosis, silicosis, tabacosis and byssinosis.

Compounds of the present invention may also be used for the treatment ofinflammatory bowel disease including Crohn's disease and ulcerativecolitis, irritable bowel syndrome, pancreatitis, nephritis, cystitis(interstitial cystitis), uveitis, inflammatory skin disorders such aspsoriasis and eczema, rheumatoid arthritis and edema resulting fromtrauma associated with burns, sprains or fracture, cerebral edema andangioedema. They may be used to treat diabetic vasculopathy, diabeticneuropathy, diabetic retinopathy, post capillary resistance or diabeticsymptoms associated with insulitis (e.g. hyperglycemia, diuresis,proteinuria and increased nitrite and kallikrein urinary excretion).They may be used as smooth muscle relaxants for the treatment of spasmof the gastrointestinal tract or uterus. Additionally, they may beeffective against liver disease, multiple sclerosis, cardiovasculardisease, e.g. atherosclerosis, congestive heart failure, myocardialinfarct; neurodegenerative diseases, eg. Parkinson's and Alzheimersdisease, epilepsy, septic shock e.g. as antihypovolemic and/oranti-hypotensive agents, headache including cluster headache, migraineincluding prophylactic and acute use, closed head trauma, cancer,sepsis, gingivitis, osteoporosis, benign prostatic hyperplasia andhyperactive bladder. Animal models of these diseases and conditions aregenerally well known in the art, and may be suitable for evaluatingcompounds of the present invention for their potential utilities.Finally, compounds of the present invention are also useful as researchtools (in vivo and in vitro).

The compounds of this invention are useful in the treatment of pain andinflammation by the administration of a tablet, cachet, or capsule eachcontaining, for example, 0.1 mg, 0.5 mg, 1 mg, 3 mg, 5 mg, 10 mg, 25 mg,50 mg, 100 mg, 125 mg, 250 mg, or 500 mg of a compound of this inventiononce every three to four hours, once, twice or three times a day, or (inan extended release formulation) once, twice or three times a week.

The compounds would be effective in the treatment or prevention of painincluding, for example, bone and joint pain (osteoarthritis), repetitivemotion pain, dental pain, cancer pain, myofascial pain (muscular injury,fibromyalgia), perioperative pain (general surgery, gynecological) andchronic pain by the administration of a tablet, cachet, or capsule eachcontaining, for example, 0.1 mg, 0.5 mg, 1 mg, 3 mg, 5 mg, 10 mg, 25 mg,50 mg, 100 mg, 125 mg, 250 mg, or 500 mg of a compound of this inventiononce every three to four hours, once, twice or three times a day, or (inan extended release formulation) once, twice or three times a week.

In particular, inflammatory pain such as, for example, inflammatoryairways disease (chronic obstructive pulmonary disease) would beeffectively treated by the compounds of this invention by theadministration of a tablet, cachet, or capsule each containing, forexample, 0.1 mg, 0.5 mg, 1 mg, 3 mg, 5 mg, 10 mg, 25 mg, 50 mg, 100 mg,125 mg, 250 mg, or 500 mg of a compound of this invention once everythree to four hours, once, twice or three times a day, or (in anextended release formulation) once, twice or three times a week.

Further, the compounds of this invention can additionally be used totreat asthma, inflammatory bowel disease, rhinitis, pancreatitis,cystitis (interstitial cystitis), uveitis, inflammatory skin disorders,rheumatoid arthritis and edema resulting from trauma associated withburns, sprains or fracture by the administration of a tablet, cachet, orcapsule each containing, for example, 0.1 mg, 0.5 mg, 1 mg, 3 mg, 5 mg,10 mg, 25 mg, 50 mg, 100 mg, 125 mg, 250 mg, or 500 mg of a compound ofthis invention once every three to four hours, once, twice or threetimes a day, or (in an extended release formulation) once, twice orthree times a week.

They may be used subsequent to surgical intervention (e.g. aspost-operative analgesics) and to treat inflammatory pain of variedorigins (e.g. osteoarthritis, rheumatoid arthritis, rheumatic disease,teno-synovitis and gout) as well as for the treatment of pain associatedwith angina, menstruation or cancer by the administration of a tablet,cachet, or capsule each containing, for example, 0.1 mg, 0.5 mg, 1 mg, 3mg, 5 mg, 10 mg, 25 mg, 50 mg, 100 mg, 125 mg, 250 mg, or 500 mg of acompound of this invention once every three to four hours, once, twiceor three times a day, or (in an extended release formulation) once,twice or three times a week.

They may be used to treat diabetic vasculopathy, post capillaryresistance or diabetic symptoms associated with insulitis (e.g.hyperglycemia, diuresis, proteinuria and increased nitrite andkallikrein urinary excretion) by the administration of a tablet, cachet,or capsule each containing, for example, 0.1 mg, 0.5 mg, 1 mg, 3 mg, 5mg, 10 mg, 25 mg, 50 mg, 10 mg, 125 mg, 250 mg, or 500 mg of a compoundof this invention once every three to four hours, once, twice or threetimes a day, or (in an extended release formulation) once, twice orthree times a week.

They may be used to treat inflammatory skin disorders such as psoriasisand eczema by the administration of a tablet, cachet, or capsule eachcontaining, for example, 0.1 mg, 0.5 mg, 1 mg, 3 mg, 5 mg, 10 mg, 25 mg,50 mg, 100 mg, 125 mg, 250 mg, or 500 mg of a compound of this inventiononce every three to four hours, once, twice or three times a day, or (inan extended release formulation) once, twice or three times a week.

They may be used as smooth muscle relaxants for the treatment of spasmof the gastrointestinal tract or uterus or in the therapy of Crohn'sdisease, ulcerative colitis or pancreatitis by the administration of atablet, cachet, or capsule each containing, for example, 0.1 mg, 0.5 mg,1 mg, 3 mg, 5 mg, 10 mg, 25 mg, 50 mg, 100 mg, 125 mg, 250 mg, or 500 mgof a compound of this invention once every three to four hours, once,twice or three times a day, or (in an extended release formulation)once, twice or three times a week.

Such compounds may be used therapeutically to treat hyperreactiveairways and to treat inflammatory events associated with airways diseasee.g. asthma, and to control, restrict or reverse airways hyperreactivityin asthma by the administration of a tablet, cachet, or capsule eachcontaining, for example, 0.1 mg, 0.5 mg, 1 mg, 3 mg, 5 mg, 10 mg, 25 mg,50 mg, 100 mg, 125 mg, 250 mg, or 500 mg of a compound of this inventiononce every three to four hours, once, twice or three times a day, or (inan extended release formulation) once, twice or three times a week.

They may be used to treat intrinsic and extrinsic asthma includingallergic asthma (atopic or non-atopic) as well as exercise-inducedbroncho-constriction, occupational asthma, viral or bacterialexacerbated asthma, other non-allergic asthmas and “wheezy-infantsyndrome” by the administration of a tablet, cachet, or capsule eachcontaining, for example, 0.1 mg, 0.5 mg, 1 mg, 3 mg, 5 mg, 10 mg, 25 mg,50 mg, 100 mg, 125 mg, 250 mg, or 500 mg of a compound of this inventiononce every three to four hours, once, twice or three times a day, or (inan extended release formulation) once, twice or three times a week.

They may also be effective against pneumoconiosis, including aluminosis,anthracosis, asbestosis, chalicosis, ptilosis, siderosis, silicosis,tabacosis and byssinosis was well as adult respiratory distresssyndrome, chronic obstructive pulmonary or airways disease, bronchitis,allergic rhinitis, and vasomotor rhinitis by the administration of atablet, cachet, or capsule each containing, for example, 0.1 mg, 0.5 mg,1 mg, 3 mg, 5 mg, 10 mg, 25 mg, 50 mg, 100 mg, 125 mg, 250 mg, or 500 mgof a compound of this invention once every three to four hours, once,twice or three times a day, or (in an extended release formulation)once, twice or three times a week.

Additionally, they may be effective against liver disease, multiplesclerosis, atherosclerosis, Alzheimer's disease, septic shock e.g. asanti-hypovolemic and/or anti-hypotensive agents, cerebral edema,headache including cluster headache, migraine including prophylactic andacute use, closed head trauma, irritable bowel syndrome and nephritis bythe administration of a tablet, cachet, or capsule each containing, forexample, 0.1 mg, 0.5 mg, 1 mg, 3 mg, 5 mg, 10 mg, 25 mg, 50 mg, 100 mg,125 mg, 250 mg, or 500 mg of a compound of this invention once everythree to four hours, once, twice or three times a day, or (in anextended release formulation) once, twice or three times a week.

Combination Therapy

Compounds of Formula I may be used in combination with other drugs thatare used in the treatment/prevention/suppression or amelioration of thediseases or conditions for which compounds of Formula I are useful. Suchother drugs may be administered, by a route and in an amount commonlyused therefor, contemporaneously or sequentially with a compound ofFormula I. When a compound of Formula I is used contemporaneously withone or more other drugs, a pharmaceutical composition containing suchother drugs in addition to the compound of Formula I is preferred.Accordingly, the pharmaceutical compositions of the present inventioninclude those that also contain one or more other active ingredients, inaddition to a compound of Formula I. Examples of other activeingredients that may be combined with a compound of Formula I, eitheradministered separately or in the same pharmaceutical compositions,include, but are not limited to: (1) morphine and other opiate receptoragonists including propoxyphene (Darvon); (2) non-steroidalantiinflammatory drugs (NSAIDs) including COX-2 inhibitors such aspropionic acid derivatives (alminoprofen, benoxaprofen, bucloxic acid,carprofen, fenbufen, fenoprofen, fluprofen, flurbiprofen, ibuprofen,indoprofen, ketoprofen, miroprofen, naproxen, oxaprozin, pirprofen,pranoprofen, suprofen, tiaprofenic acid, and tioxaprofen), acetic acidderivatives (indomethacin, acemetacin, alclofenac, clidanac, diclofenac,fenclofenac, fenclozic acid, fentiazac, furofenac, ibufenac, isoxepac,oxpinac, sulindac, tiopinac, tolmetin, zidometacin, and zomepirac),fenamic acid derivatives (flufenamic acid, meclofenamic acid, mefenamicacid, niflumic acid and tolfenamic acid), biphenylcarboxylic acidderivatives (diflunisal and flufenisal), oxicams (isoxicam, piroxicam,sudoxicam and tenoxican), salicylates (acetyl salicylic acid,sulfasalazine) and the pyrazolones (apazone, bezpiperylon, feprazone,mofebutazone, oxyphenbutazone, phenylbutazone), and the coxibs(celecoxib, valecoxib, rofecoxib and etoricoxib); (3) corticosteroidssuch as betamethasone, budesonide, cortisone, dexzimethasone,hydrocortisone, methylprednisolone, prednisolone, prednisone andtriamcinolone; (4) histamine H1 receptor antagonists such asbromopheniramine, chlorpheniramine, dexchlorpheniramine, triprolidine,clemastine, diphenhydramine, diphenylpyraline, tripelennamine,hydroxyzine, methdilazine, promethazine, trimeprazine, azatadine,cyproheptadine, antazoline, pheniramine pyrilamine, astemizole,terfenadine, loratadine, cetirizine, desloratadine, fexofenadine andlevocetirizine; (5) histamine H2 receptor antagonists such ascimetidine, famotidine and ranitidine; (6) proton pump inhibitors suchas omeprazole, pantoprazole and esomeprazole; (7) leukotrieneantagonists and 5-lipoxygenase inhibitors such as zafirlukast,montelukast, pranlukast and zileuton; (8) drugs used for angina,myocardial ischemia including nitrates such as nitroglycerin andisosorbide nitrates, beta blockers such as atenolol, metoprolol,propranolol, acebutolol, betaxolol, bisoprolol, carteolol, labetalol,nadolol, oxprenolol, penbutolol, pindolol, sotalol and timolol, andcalcium channel blockers such as diltiazam, verapamil, nifedipine,bepridil, felodipine, flunarizine, isradipine, nicardipine andnimodipine; (9) incontinence medications such as antimuscarinics, e.g.,tolterodine and oxybutinin); (10) gastrointestinal antispasmodics (suchas atropine, scopolamine, dicyclomine, antimuscarinics, as well asdiphenoxylate); skeletal muscle relaxants (cyclobenzaprine,carisoprodol, chlorphenesin, chlorzoxazone, metaxalone, methocarbamol,baclofen, dantrolene, diazepam, or orphenadrine); (11) gout medicationssuch as allopurinol, probenicid and colchicine; (12) drugs forrheumatoid arthritis such as methotrexate, auranofin, aurothioglucoseand gold sodium thiomalate; (13) drugs for osteoporosis such asalendronate and raloxifene; decongestants such as pseudoephedrine andphenylpropanolamine; (14) local anesthetics; (15) anti-herpes drugs suchas acyclovir, valacyclovir and famcyclovir; and (15) anti-emetics suchas ondansetron and granisetron.

Biological Evaluation

Assessing the Affinity of Selected Compounds to Bind to the BradykininB1 or B2 Receptor

Radioligand binding assays are performed using membranes from CHO cellsthat stably express the human, rabbit, rat, or dog B1 receptors or CHOcells that express the human B2 receptor. For all receptor types, cellsare harvested from culture flasks in PBS/1 mM EDTA and centrifuged at1000×g for 10 minutes. The cell pellets are homogenized with a polytronin ice cold 20 mM HEPES, 1 nM EDTA, pH 7.4 (lysis buffer) andcentrifuged at 20,000×g for 20 minutes. The membrane pellets arerehomogenized in lysis buffer, centrifuged again at 20,000×g and thefinal pellets are resuspended at 5 mg protein/ml in assay buffer (120 mMNaCl, 5 mM KCl, 20 mM BEPES, pH 7.4) supplemented with 1% BSA and frozenat −80° C.

On the day of assay, membranes are centrifuged at 14,000×g for 5 minutesand resuspended to the desired protein concentration in assay buffercontaining 10 nM enaliprilat, 140 μg/mL bacitracin and 0.1% BSA.3H-des-arg10, leu9 kallidin is the radioligand used for the human andrabbit B1 receptors, 3H-des-arg10 kallidin is used for the rat and dogB1 receptors, and 3H-bradykinin is used to label the human B2 receptor.

For all assays, compounds are diluted from DMSO stock solutions with 4μL added to assay tubes for a final DMSO concentration of 2%. This isfollowed by the addition of 100 μL radioligand and 100 μL of themembrane suspension. Nonspecific binding for the B1 receptor bindingassays is determined using 1 μM des-arg10 kallidin and nonspecificbinding for the B2 receptor is determined with 1 μM bradykinin. Tubesare incubated at room temperature (22° C.) for 60 minutes followed byfiltration using a Tomtec 96-well harvesting system. Radioactivityretained by the filter is counted using a Wallac Beta-platescintillation counter.

The compounds of this invention have affinity for the B1 receptor in theabove assay as demonstrated by results of less than 5 μM. It isadvantageous that the assay results be less than 1 μM, even moreadvantageous for the results be less than 0.5 μM. It is furtheradvantageous that compounds of this invention have affinity for thebradykinin B1 receptor over the bradykinin B2 receptor, moreadvantageously, the affinity for the B1 receptor is at least 10 fold,and preferably over 100 fold, over that for the B2 receptor.

Assay for Bradykinin B1 Antagonists

B1 agonist-induced calcium mobilization was monitored using aFluorescence Imaging Plate Reader (FLIPR). CHO cells expressing the B1receptor were plated in 96 or 384 well plates and allowed to incubate inIscove's modified DMEM overnight. Wells were washed two times with aphysiological buffered salt solution and then incubated with 4 uM Fluo-3for one hour at 37° C. The plates were then washed two times withbuffered salt solution and 100 uL of buffer was added to each well.Plates were placed in the FLIPR unit and allowed to equilibrate for twominutes. The test compound was then added in 50 ul volumes followed fiveminutes later by 50 ul of agonist (des-arg¹⁰ kallidin). Relativefluorescence peak heights in the absence and presence of antagonist wereused to calculate the degree of inhibition of the B1 receptor agonistresponse by the test compound. Eight to ten concentrations of testcompound were typically evaluated to construct an inhibition curve anddetermine IC50 values using a four-parameter nonlinear regression curvefitting routine.

Assay for Bradykinin Inverse Agonists

Inverse agonist activity at the human B1 receptor was evaluated usingtransiently transfected HEK293 cells. One day following transfectioncell flasks were labeled overnight with 6 uCi/ml [³H]myo-inositol. Onthe day of assay, the media was removed and the attached cells weregently rinsed with 2×20 ml of phosphate-buffered saline. Assay buffer(BEPES buffered physiological salts, pH 7.4) was added and the cellswere detached by tapping of the flask. The cells were centrifuged at800×g for five minutes and resuspended at 1×10⁶ cells/ml in assay buffersupplemented with 10 mM lithium chloride. After 10 minutes at roomtemperature, one-half ml aliquots were distributed to tubes containingtest compound or vehicle. After an additional 10 minutes the tubes weretransferred to a 37° C. water bath for 30 minutes. The incubation wasterminated by the addition of a 12% perchloric acid solution and thetubes were placed on ice for 30 minutes. The acid was then neutralizedwith KOH and the tubes centrifuged to pellet precipitated material.[³H]Inositol monophosphate formed was recovered by standard ion exchangechromatographic techniques and quantitated by liquid scintillationcounting. Inverse agonist activity was determined by the degree to whicha test compound reduced basal (cells incubated with vehicle) levels of[³H]inositol monophosphate accumulation.

Abbreviations Used

The following abbreviations have the meanings indicated, unless statedotherwise in the specification:

-   BOC (boc) t-butyloxycarbonyl-   DCM dichloromethane-   DMF dimethylformamide-   DMSO Dimethyl sulfoxide-   EDC or EDCI 1-(3-dimethylaminopropyl)₃-ethylcarbodiimide HCl-   eq. equivalent(s)-   ES (or ESI)—MS electron spray ionization—mass spectroscopy-   Et ethyl-   EtOAc ethyl acetate-   EtOH ethanol-   FAB-MS fast atom bombardment-mass spectroscopy-   HOBt 1-hydroxybenzotriazole hydrate-   HPLC high pressure liquid chromatography-   LCMS Liquid chromatography/mass spectroscopy-   LHMDS lithium bis(trimethylsilyl)amide-   Me methyl-   MeOH Methanol-   MHz megahertz-   MsCl Mesyl chloride-   NEt₃ Triethylamine-   NMR nuclear magnetic resonance-   TFA trifluoroacetic acid-   TEF tetrahydrofuran

Compounds of formula I may be prepared according to the followingillustrative schemes.

In Scheme 1, compound (Ia) is assembled by coupling thebiarylmethanamine derivative (1) to the protected aminocycloalkanoicacid (2) using standard peptide coupling reagent combinations, such asEDCI/HOBt, in an appropriate solvent, such as THF, to provide (3). TheBoc protecting group is then removed by the action of an acid, like HCl,in an appropriate solvent, like MeOH, to yield an ammonium salt fromwhich the free-base derivative (4) may be obtained using an appropriatebase, such as ammonia, and an appropriate solvent, such as chloroform.This amine derivative (4) is then reacted with a carboxylic acid orcarboxylic acid equivalent to yield title compound (Ia). Alternatively,the acid-salt of (4) can be used in the final reaction to yield titlecompound (Ia) provided an appropriate base such as triethylamine isadded.

Alternatively, compound (Ia) may be assembled by coupling thebiarylmethanamine derivative (1), with the acylated aminocycloalkanoicacid (5) as shown in Scheme 1a.

A number of synthetic strategies may be employed to assemble theintermediate biarylmethanamine derivative (1) as shown in Schemes 2a-2c.

In Scheme 2a, the cyanobiaryl derivative (8) is assembled using a Suzukireaction between an aromatic boronic acid derivative (6), or anappropriate boronic ester derivative, and an aromatic halide (7) in thepresence of a triarylphosphine, like triphenylphosphine, and a metalcatalyst, like palladium acetate.

The resultant cyano biaryl intermediate (8) is then catalyticallyreduced to the corresponding amine biaryl derivative (1a) using hydrogenand a metal, such as Raney Ni, in an appropriate solvent.

Alternatively, as illustrated in Scheme 2b, a methanamine derivative(9), after primary amine protection with an appropriate protecting groupsuch as Boc, is elaborated to the pinacol boron ester (11) using apalladium catalyst in an appropriate solvent, like dimethyl sulfoxide.This boron ester (11) is coupled to an aryl halide derivative (7)employing Suzuki reaction conditions to yield (1).

A third method for the preparation of biarylmethanamine derivatives isdepicted in Scheme 2c. The biaryl moiety (14) is first assembled using apalladium catalyzed coupling of (12) with an aryl zinc compound (13) asshown. The methyl group of biaryl (14) is then elaborated according tothe three step sequence of halogenation, nucleophilic displacement ofthe halogen with azide, and reduction to provide the corresponding amineintermediate (1a). Alternatively, the biarylmethanamine (1a) can also beprepared starting from the arylcarbonitrile (16) and aryl zinc compound(13) as previously discussed. The resulting biarylcarbonitrile (8) isthen reduced using hydrogen to provide (1a).

It will be appreciated by persons skilled in the art that functionalgroup interconversion can be used to provide various compounds offormula I. As illustrated in Scheme 3, derivative (3a) isbis-deprotected first by the action of a strong acid, like TFA, andsecond by alkaline hydrolysis in a suitable mixture of water and anorganic solvent, like methanol, at a temperature between 25 and 100° C.to yield the amino acid derivative (17). Prior activation of acarboxylic acid (R⁵COOH) with an appropriate set of peptide couplingreagents, like EDCI/HOBt, forms the ‘active ester’ which then reactswith the amino acid derivative (17) to yield (18). The latter compoundcan either react with amines (HNR^(b)R^(c)) or alkyloxy amines(H₂NOR^(a)) under the action of an appropriate set of peptide couplingreagents, like EDCI/HOBt, to form the claimed compounds (Ib) and (Ic),respectively.

N-alkylation is illustrated in Scheme 4. The amine (4) is alkylated withexcess alkyl iodide (I-R¹) in an appropriate solvent, like THF, in thepresence of an acid scavenger, like triethylamine, at elevatedtemperatures to provide (19), along with bis-alkylated material.Secondary amine (19) is then converted to the title compound by reactingwith a carboxylic acid or carboxylic acid equivalent to provide (Id).

The preparation of compounds of formula I having a 1,2-cis- or1,2-trans-cyclopropyl moiety is illustrated in Schemes 5 and 6.According to known procedures (K. Burgess et al., J. Org. Chem.,57:5931–5936(1992)), di-tert-butyl malonate is elaborated to derivative(20). The N-Boc group is removed using methane sulfonic acid accordingto L. S. Lin et al. Tetrahedron Lett., 41:7013–7016(2000) to give amine(21). This amine is allowed to react with a carboxylic acid orcarboxylic acid equivalent under appropriate peptide coupling conditionsto yield (22). The tert-butyl ester is then cleaved with an acid, likeTFA, in an appropriate solvent, like DCM, to provide acid (23).Biarylmethanamine (1) is then coupled with the acid (23) using anappropriate set of peptide coupling reagents, like EDCI/HOBt, to producethe title compound (Ie). Further elaboration of (Ie) to additionalcompounds of formula I may be accomplished using procedures well knownto those skilled in the art. For example, the acetyl group may beremoved by hydrolysis to provide the corresponding alcohol; the alcoholmay be converted to the corresponding sulfonate by treatment withsulfonyl chloride, and the sulfonate may be converted to thecorresponding halide by treatment with a source of the halide. These andother functional transformations to provide compounds of formula I aredescribed in typical organic chemistry textbooks such as March'sAdvanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5^(th)Ed., John Wiley & Sons, 2000.

In Scheme 6, according to known procedures (K. Burgess et al., J. Org.Chem., 57:5931–5936(1992)), di-tert-butyl malonate is elaborated toderivative (24). The N-Boc group is removed using an acid, like TFA, inan appropriate solvent, like DCM. This amine is allowed to react with acarboxylic acid or carboxylic acid equivalent under appropriate peptidecoupling conditions, like EDCI/HOBt/NEt₃ to yield (25).Biarylmethanamine (1), is then allowed to open the lactone (25) in anappropriate aprotic solvent, like DMF, at a temperature between 20 and100° C., to produce the title compound (If). Further elaboration of (If)to additional title compounds may be accomplished using procedures wellknown to those skilled in the art as previously discussed.

Reference Procedure 1 Methyl3-fluoro-4′-{(1R)-1-[({1-[(3,3,3-trifluoropropanoyl)amino]cyclopropyl}-carbonyl)amino]ethyl}-1,1′-biphenyl-2-carboxylate

Commercially available (1R)-1-(4-bromophenyl)ethanamine was Bocprotected, using standard procedures known to those skilled in the art,to produce tert-butyl (1R)-1-(4-bromophenyl)ethylcarbamate.

To a solution of tert-butyl (1R)-1-(4-bromophenyl)ethylcarbamate (7.6 g,25.3 mmol) in DMSO (20 mL) was added bis(pinacolato)diboron (7.07 g,27.9 mmol), dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II)dichloro-methane adduct (2.06 g, 2.53 mmol), and potassium acetate (7.45g, 76.0 mmol) at room temperature under N₂. The resulting mixture washeated at 80° C. for 1 hour. The reaction was quenched by addition ofEtOAc and filtered through celite. The organic extract was washed withwater three times, saturated NaCl, dried over MgSO₄, filtered andconcentrated under vacuum. The residue was purified on silica gel elutedwith 0–20% ethyl acetate in hexane to provide tert-butyl(1R)-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethylcarbamateas a clear light yellow oil with a mass ion (ES+) of 333.

To a stirred solution of tert-butyl(1R)-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethylcarbamate(1.0 g, 2.9 mmol) and methyl 2-fluoro-6-iodobenzoate (1.2 g, 4.32 mmol)in 25 mL of a 5:1 THF:water mixture was added potassium carbonate (1.2g, 8.64 mmol), tri-o-tolylphosphine (350 mg, 1.15 mmol) and lastlypalladium acetate (65 mg, 0.29 mmol). The reaction vessel was thensealed and placed into a 90° C. oil bath for overnight stirring andheating. After about 18 hours the reaction mixture was cooled to ambienttemperature and then diluted with EtOAc. The organics were washed withbrine (×4), dried over sodium sulfate, filtered, and concentrated underreduced pressure to give an oil. This oil was subject to silica gelchromatography eluting with 10–60% EtOAc in hexanes to provide methyl4′-{(1R)-1-[(tert-butoxycarbonyl)amino]ethyl}-3-fluoro-1,1′-biphenyl-2-carboxylate(205 mg), found to be pure by LC/MS and proton NMR.

Methyl4′-{(1R)-1-[(tert-butoxycarbonyl)amino]ethyl}-3-fluoro-1,1′-biphenyl-2-carboxylate(205 mg, 0.60 mmol) dissolved in MeOH (15 mL) was cooled to 0° C. Thishomogenous solution was saturated with anhydrous hydrogen chloride andallowed to sit for 20 minutes. Dry nitrogen was then bubbled through thesolution for about 30 minutes. Solvent was then removed under reducedpressure to yield an oily residue. The oil was then dissolved in DCM andthe solvent removed. This process was repeated until a solid aminehydrochloride was obtained.

The above amine hydrochloride (85 mg, 0.27 mmol) along with1-[(tert-butoxycarbonyl)amino]cyclopropanecarboxylic acid (55 mg, 0.27mmol), HOBt.H₂O (8.4 mg, 0.05 mmol) and triethylamine (33 mg, 0.33 mmol)were dissolved in 4.5 mL of THF. To this room-temperature solution wasadded EDCI (74 mg, 0.38 mmol). After overnight stirring (ca. 16.5 h) thereaction mixture was diluted with water and EtOAc. The organic layer waswashed successively with 1N HCl, 5% sodium bicarbonate, half-brine (×3)and then brine. The organic layer was dried over sodium sulfate,filtered and evaporated under reduced pressure to obtain a residue whichwas subjected to silica gel chromatography eluting with 1–6% MeOH inDCM. Collection of product containing fractions and removal of solventyielded 108 mg (86%) of methyl4′-{(1R)-1-[({1-[(tert-butoxycarbonyl)amino]cyclopropyl}carbonyl)-amino]ethyl}-3-fluoro-1,1′-biphenyl-2-carboxylate.

Methyl 4′-{(1R)-1-[({1-[(tert-butoxycarbonyl)amino]cyclopropyl}-carbonyl)amino]ethyl}-3-fluoro-1,1′-biphenyl-2-carboxylate (108 mg,0.24 mmol) dissolved in MeOH (5.0 mL) was cooled to 0° C. Thishomogenous solution was saturated with anhydrous hydrogen chloride andallowed to sit for 30 minutes. Dry nitrogen was then bubbled through thesolution for about 50 min. Solvent was then removed under reducedpressure to yield an oily residue. The oil was then dissolved in DCM andthe solvent removed. This process being repeated until a solid aminehydrochloride was obtained.

The above amine hydrochloride (46 mg, 0.12 mmol) along withtrifluoropropionic acid (15 mg, 0.12 mmol), HOBt.H₂O (3.6 mg, 0.02 mmol)and triethylarine (14 mg, 0.14 mmol) were dissolved in 1.6 mL of THFplus 1.6 mL of DMF. To this room-temperature solution was added EDCI (31mg, 0.16 mmol). After overnight stirring (ca. 18 h) the reaction mixturewas diluted with water and EtOAc. The organic layer was washedsuccessively with 1N HCl, 5% sodium bicarbonate, half-brine (×3) andthen brine. The organic layer was dried over sodium sulfate, filteredand evaporated under reduced pressure to obtain a residue which wassubjected to silica gel chromatography eluting with 1–12% MeOH in DCM.Collection of product containing fractions and removal of solventyielded 36 mg (67%) of the title compound as a foaming solid. Purity wasdetermined by LCMS (ES MS, M+H⁺ found:467) and proton NMR (400 Mz,CD₃OD: δ 7.555, 7.540, 7.535, 7.520, 7.515, 7.500, 7.393, 7.373, 7.319,7.302, 7.298, 7.240, 7.222, 7.221, 7.211, 7.188, 7.167, 7.165, 5.116,5.099, 5.081, 5.064, 3.659, 3.268, 3.241, 3.214, 3.187, 1.508, 1.490,1.483, 1.477, 1.474, 1.470, 1.465, 1.454, 1.444, 1.056, 1.049, 1.036,1.031, 1.023, 1.007, 0.999, 0.995, 0.982, 0.974).

Reference Procedure 23-Fluoro-N-methoxy-4′-{(1R)-1-[({1-[(3,3,3-trifluoropropanoyl)amino]cyclopropyl}-carbonyl)amino]ethyl}-1,1′-biphenyl-2-carboxamide

A solution of methyl4′-{(1R)-1-[({1-[(tert-butoxycarbonyl)amino]-cyclopropyl}carbonyl)amino]ethyl}-3-fluoro-1,1′-biphenyl-2-carboxylate(466 mg, 1.0 mmol) in DCM (15 mL) and TFA (15 mL) was stirred under N₂for 20 minutes at ambient temperature, then the organic solvent wasremoved under vacuum. The residue was dissolved in MeOH (20 mL), 4N NaOH(10 mL) and water (10 mL). This mixture was heated at reflux for 4 hoursand then neutralized with 6N HCl. Purification was achieved bypreparative HPLC on a delta-pack C₁₈ column, 300 Å, pore size 15 μM with0.05% HCl acid-aqueous acetonitrile solvent systems using various lineargradients. Fractions containing product of 99% purity as measured byHPLC were combined and lyophilized to give4′-((1R)-1-{[(1-aminocyclopropyl)-carbonyl]amino}ethyl)-3-fluoro-1,1′-biphenyl-2-carboxylicacid as a white solid.

To a solution of trifluoropropionic acid (128 mg, 1.0 mmol) in DCM (1mL), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (229 mg,1.2 mmol) and 1-hydroxy-7-azabenzotriazole (136 mg, 1.0 mmol) wereadded. The resulting solution was stirred at room temperature for 20minutes, then4′-((1R)-1-{[(1-aminocyclopropyl)carbonyl]amino}ethyl)-3-fluoro-1,1′-biphenyl-2-carboxylicacid (171 mg, 0.5 mmol) in 1 mL DCM was added, followed byN,N-diisopropylethylamine until pH=10 was achieved. The reaction mixturewas stirred at ambient temperature under N₂ for 2 hours, concentratedunder vacuum and then partitioned between water and ethyl acetate. Theorganic extract was washed with brine, dried over anhydrous magnesiumsulfate, filtered and concentrated under vacuum. The residue wassubjected to column chromatography on silica gel eluted with 40% MeOH inCHCl₃. Collection and concentration of appropriate fractions provided3-fluoro-4′-{(1R)-1-[({1-[(3,3,3-trifluoropropanoyl)amino]cyclopropyl}carbonyl)-amino]ethyl}-1,1′-biphenyl-2-carboxylicacid as a white powder.

To a solution of the above acid (226 mg, 0.50 mmol) in DCM (1 mL),1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (134 mg, 0.70mmol), 1-hydroxy-7-azabenzotriazole (68 mg, 0.50 mmol) and methoxyaminehydrochloride (167 mg, 1.0 mmol) were added, followed byN,N-diisopropylethylamine until pH=10 was achieved. The resultingsolution was stirred at room temperature for 2 hours, and thenpartitioned between ethyl acetate and water. The organic extract waswashed with brine, dried over anhydrous magnesium sulfate, filtered andconcentrated under vacuum. Purification was achieved by preparative HPLCon a delta-pack C₁₈ column with 0.05% HCl acid-aqueous acetonitrilesolvent systems using various linear gradients. Fractions containingproduct of 99% purity as measured by HPLC were combined and lyophilizedto give the title compound as a white solid. Purity was determined byLCMS (ES MS, M+H⁺ found:482) and proton NMR (400 MHz, DMSO-d₆) δ 1.40(d, J=7.1 Hz, 3H), 0.60–0.80 (m, 2H), 1.27 (m, 2H), 3.23 (m, J=11.2 Hz,2H). 3.44 (s, 3H), 5.02 (q, J=8 Hz, 1H), 7.25–7.39 (m, 6H), 7.52 (m,1H), 7.93 (d, J=8.2 Hz, 1H), 8.89 (s, 1H).

The following examples are provided to illustrate the invention withoutlimiting the invention to the particulars of these examples. Compoundswere named using: ACD/Name version 4.53 (Advanced Chemistry DevelopmentInc.© 1994–2000). Address: 90 Adelaide Street West, Toronto, Ontario,M5H 3V9, Canada.

EXAMPLE 1 Methyl4′-{[({1-[(3,3,3-trifluoropropanoyl)amino]cyclopropyl}carbonyl)amino]-methyl}-1,1′-biphenyl-2-carboxylate

To 500 mL of THF was added water (18.4 mL, 1.02 mol), potassiumcarbonate (70.5 g, 0.510 mol), methyl 2-iodobenzoate (53.5 g, 0.204mol), 4-cyano-phenylboronic acid (30.0 g, 0.204 mol) andbis-(tri-o-tolylphosphine) palladium (II) chloride (1.65 g, 2.04 mmol).This mixture was heated to reflux for 3.5 hours and then cooled toambient temperature for continued stirring overnight. The solvent wasthen removed under reduced pressure prior to dilution with EtOAc/water.The organic layer was extracted with additional EtOAc. The combinedorganics were washed with water, then brine. The organics were thendried over sodium sulfate, filtered, and then concentrated to obtain thecrude product. This crude product was passed through a silica pad,eluting with 8:1 heptane:EtOAc to get 41.6 grams of methyl4′-cyano-1,1′-biphenyl-2-carboxylate.

To a stirred solution of methyl 4′-cyano-1,1′-biphenyl-2-carboxylate(50.0 g, 0.211 mol) in 2M ammonia in methanol (500 mL) was addedapproximately 5 teaspoons of a 50% aqueous slurry of Raney Nickel(Aldrich). The reaction vessel was purged with nitrogen and then flushedwith hydrogen from a balloon. After 6 hours of stirring under a freshballoon, the balloon was recharged and stirring was continued for anadditional 3 hours. Nitrogen was bubbled through the solution for 15minutes prior to filtration through a celite pad. Solvent was removedand 1 L of diethyl ether was added with stirring. This solution wasfiltered and the solvent removed. The residue was now dissolved in a 1:1mixture of diethyl ether:EtOAc prior to introduction of anhydroushydrogen chloride (until no additional precipitate forms). The solid wasfiltered and dried in a vacuum oven over the weekend; providing 56.1grams of methyl 4′-(aminomethyl)-1,1′-biphenyl-2-carboxylatehydrochloride, which gave LC/MS and proton NMR spectra consistent withtheory.

The free-base of the above mentioned amine hydrochloride (0.51 g, 2.1mmol), was dissolved in anhydrous THF (21 mL). To this stirred solutionwas added 1-[(tert-butoxycarbonyl)amino-9 cyclopropanecarboxylic acid(0.51 g, 2.5 mmol), triethylamine (0.30 g, 3.0 mmol), HOBt.H₂O (65 mg,0.42 mmol) and lastly EDCI (0.57 g, 3.0 mmol). This mixture was allowedto stir overnight. Solvent was then removed under reduced pressure andthe residue was subjected to silica gel chromatography eluting with a1–10% MeOH in DCM gradient to provide methyl4′-{[({1-[(tert-butoxycarbonyl)amino]cyclopropyl}carbonyl)amino]methyl}-1,1′-biphenyl-2-carboxylate(0.84 g), giving LC/MS and proton NMR spectra consistent with theory.

Methyl4′-{[({1-[(tert-butoxycarbonyl)amino]cyclopropyl}carbonyl)-amino]methyl}-1,1′-biphenyl-2-carboxylate(0.84 g, 2.0 mmol) dissolved in a mixture of DCM (3 mL) and MeOH (45 mL)was cooled to 0° C. This homogenous solution was saturated withanhydrous hydrogen chloride and allowed to sit for 30 minutes. Drynitrogen was then bubbled through the solution for about 30 min. Solventwas then removed under reduced pressure to yield an oily residue. Theoil was then dissolved in DCM and the solvent removed. This processbeing repeated until a solid amine hydrochloride was obtained.Alternatively, the residue could be dissolved in chloroform followed bysaturation with ammonia gas, filtration and solvent removal to obtainsolid methyl4′-({[(1-aminocyclopropyl)carbonyl]amino}methyl)-1,1′-biphenyl-2-carboxylateas the free-base.

To a room temperature, stirred solution of the above mentioned aminehydrochloride (0.15 g, 0.42 mmol) in DMF (2.8 mL) was added HOBtH₂O (13mg, 0.08 mmol), trifluoropropionic acid (64 mg, 0.50 mmol),triethylamine (100 mg, 1.0 mmol) and lastly EDCI (110 mg, 0.58 mmol).After overnight stirring (ca. 17 h) the reaction mixture was dilutedwith water and EtOAc. The organic layer was washed successively with 1NHCl, 5% sodium bicarbonate, half-brine (×3) and then brine. The organiclayer was dried over sodium sulfate, filtered and evaporated underreduced pressure to obtain a residue which was subject to silica gelchromatography eluting with 1–12% MeOH in DCM. Collection of productcontaining fractions and removal of solvent yielded 141 mg (78%) of thetitle compound as a foaming solid. Purity was determined by LCMS (ES MS,M+₊H₂O found:452) and proton NMR (400 MHz, CD₃OD: δ 7.748, 7.745, 7.729,7.726, 7.560,7.557, 7.541, 7.538, 7.446, 7.443, 7.427, 7.424, 7.380,7.361, 7.323, 7.302, 7.238, 7.218, 4.461, 3.608, 3.249, 3.222, 3.195,3.168, 1.532, 1.521, 1.513, 1.501, 1.048, 1.037, 1.029, 1.017).

EXAMPLE 2 Methyl4′-{[({1-[methyl(3,3,3-trifluoropropanoyl)amino]cyclopropyl}carbonyl)-amino]methyl}-1,1′-biphenyl-2-carboxylate

Methyl4′-({[(1-aminocyclopropyl)carbonyl]amino}methyl)-1,1′-biphenyl-2-carboxylate(200 mg, 0.62 mmol), prepared according to Example 1, was dissolved in 5mL of DCM along with iodomethane (130 mg, 0.93 mmol) and triethylamine(75 mg, 0.74 mmol). After no reaction was observed at ambienttemperature, the reaction mixture was heated to reflux for about twodays. After the first day, additional iodomethane was added (ca. 3–5equiv.). After two days >50% of the starting material was consumed. Thereaction mixture was concentrated under reduced pressure and the residuewas subjected to silica gel chromatography eluting with 1–10% MeOH inDCM to afford 73 mg of methyl4′-[({[1-(methylamino)cyclo-propyl]carbonyl}amino)methyl]-1,1′-biphenyl-2-carboxylate.

The above secondary amine (73 mg, 0.22 mmol) along withtrifluoropropionic acid (42 mg, 0.32 mmol) and HOBt.H₂O (40 mg, 0.26mmol) were dissolved in a minimal amount of a 1:1 DCM:TBF solution. Tothis room-temperature solution was added EDCI (54 mg, 0.28 mmol). Afterovernight stirring (ca. 18 h) the reaction was about 66% complete.Additional trifluoropropionic acid (42 mg), HOBt.H₂O (40 mg) and EDCI(54 mg) were added and the reaction mixture was allowed to stir foranother day. Solvent was removed from the reaction mixture and theresidue was subjected to silica gel chromatography eluting with 1–4%MeOH in DCM to obtain only partial purification. A second attempt atsilica gel chromatography eluting with 25–75% EtOAc in hexane,collection of product containing fractions and removal of solvent gavethe title compound. Purity was determined by LCMS (ES MS, M+H⁺found:449) and proton NMR (400 MHz, CDCl₃(rotomers present): δ 7.856,7.837, 7.818, 7.557, 7.554, 7.538, 7.535, 7.519, 7.516, 7.439, 7.436,7.420, 7.401, 7.357, 7.338, 7.305, 7.284, 7.269, 7.261 (CHCl₃), 7.249,6.341, 4.526, 4.520, 4.512, 4.506, 4.495, 3.658, 3.356, 3.339, 3.330,3.315, 3.291, 3.267, 3.256, 3.244, 3.232, 3.135, 3.048, 2.094, 2.085,2.068, 2.059, 1.685, 1.667, 1.657, 1.640, 1.630, 1.318, 1.291, 1.279,1.273, 1.260, 1.242, 1.238, 1.229, 1.221, 1.211, 1.194, 1.184).

EXAMPLE 3 Methyl4′-{[({(±)-cis-(acetyloxy)methyl]-1-[(3,3,3-trifluoropropanoyl)amino]-cyclopropyl}carbonyl)amino]methyl}-1,1′-biphenyl-2-carboxylate

tert-Butyl(±)-cis-(acetyloxy)methyl]-1-[(tert-butoxycarbonyl)amino]-cyclopropanecarboxylate (1.77 g, 5.38 mmol) was dissolved in 25 mL of tert-butylacetate and 5.75 mL of methylene chloride. The solution was stirred atambient temperature and 700 μL (10.8 mmol) methanesulfonic acid wasadded. After stirring overnight, TLC analysis (hexane-ethyl acetate,75–25) indicated that no starting material remained. Saturated sodiumbicarbonate solution was added to bring the pH of reaction mixture to7.5 and the aqueous phase was extracted with ethyl acetate (3×75 mL).The combined organic extracts were dried (sodium sulfate) andconcentrated to yield 523 mg of tert-butyl(±)-cis-(acetyloxy)methyl]-1-aminocyclopropanecarboxylate.

The above amine (523 mg, 2.28 mmol) was mixed with3,3,3-trifluoropropionic acid (366 mg, 2.86 mmol) in 4.6 mL ofN,N-dimethylformamide. N-Hydroxybenzotriazole (455 mg, 2.97 mmol) wasadded, followed by 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (569mg, 2.97 mmol). The pH of the reaction mixture was adjusted to 8.5 withtriethylamine and the mixture was allowed to stir for 2 hours at ambienttemperature. The reaction was treated with 20 ml of a 50% sodiumbicarbonate solution and was extracted with ethyl acetate (3×75 mL). Thecombined organic extracts were washed with water and brine, then dried(sodium sulfate) and concentrated in vacuo to give the crude product.This material was applied to a 35 g ISCO column and eluted with 5–20%ethyl acetate in hexane to yield 500 mg (65%) of tert-butyl(O)-cis-(acetyloxy)methyl]-1-[(3,3,3-trifluoropropanoyl)amino]cyclopropanecarboxylate.

tert-Butyl(±)-cis-(acetyloxy)methyl]-1-[(3,3,3-trifluoropropanoyl)-amino]cyclopropanecarboxylate (489 mg, 1.44 mmol) was dissolved in a mixture of 4 mL ofmethylene chloride and 1.22 mL of trifluoroacetic acid. The reactionmixture was allowed to stir at ambient temperature for 3.5 hours. Thesolvents were removed in vacuo and the residue was azeotroped withtoluene (450 ml) to afford 408 mg of(±)-cis-(acetyloxy)methyl]-1-[(3,3,3-trifluoropropanoyl)amino]cyclopropane-carboxylicacid.

(±)-cis-(Acetyloxy)methyl]-1-[(3,3,3-trifluoropropanoyl)amino]-cyclopropanecarboxylic acid (408 mg, 1.44 mmol) was mixed with methyl4′-(aminomethyl)-1,1′-biphenyl-2-carboxylate (418 mg, 1.73 mmol) in 3 mLof N,N-dimethylformamide. N-Hydroxybenzotriazole (265 mg, 1.73 mmol) wasadded, followed by 1ethyl-3-(3-dimethylaminopropyl)carbodiimide (332 mg,1.73 mmol). The mixture was adjusted to pH 8.5 with triethylamine andallowed to stir at room temperature for 2 hours. Water (10 mL) was addedand the mixture was extracted with ethyl acetate (3×50 mL). The combinedorganic extracts were washed with water and dried (sodium sulfate), thenconcentrated in vacuo to afford 700 mg of the crude product. Thismaterial was chromatographed on silica gel to give 500 mg (69%) of titlecompound. Purity was determined by LCMS (ES MS, M+H⁺ found:507) andproton NMR (400 MHz, CDCl₃) δ 0.85–0.87 (dd, 1H), 1.92–1.95 (dd, 1H),2.1–2.17 (m, 1H), 2.13 (s, 3H), 3.15 (dd, 2H, CH ² CF₃), 3.66 (s, 3H),4.0 (dd, 1H), 4.31 (dd, 1H), 4.49 (m, 2H, CH ² C₆H₄—), 6.61 (dd, 1H,NH), 7.27 (m, 4H), 7.35 (d, 1H), 7.41 (ddd, 1H), 7.53 (ddd, 1H), 7.81(d, 1H), 8.3 (s, 1H, NH).

EXAMPLE 4 Methyl4′-{[({(±)-trans-2-(hydroxymethyl)-1-[(3,3,3-trifluoropropanoyl)amino]-cyclopropyl}carbonyl)amino]methyl}-1,1′-biphenyl-2-carboxylate

tert-Butyl (±)-trans-2-oxo-3-oxabicyclo[3.1.0]hex-1-ylcarbamate (241 mg,1.13 mmol) was dissolved in a 3:1 mixture of methylenechloride:trifluoroacetic acid. The solution was stirred at ambienttemperature for two hours. The solvents were removed in vacuo and theresidue was taken up in 150 mL of ethyl acetate. The ethyl acetatesolution was washed with a 50% sodium bicarbonate solution and brine,then dried (sodium sulfate) and concentrated to afford 128 mg of(O)-trans-1-amino-3-oxabicyclo[3.1.0]hexan-2-one.

(±)-Trans-1-amino-3-oxabicyclo[3.1.0]hexan-2-one (128 mg, 1.13 mmol) wasmixed with 3,3,3-trifluoropropionic acid in 2.3 mL ofN,N-dimethylformamide. Hydroxybenzotriazole (17.4 mg, 0.11 mmol) wasadded followed by 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (282 mg,1.47 mmol). The pH of the reaction mixture was adjusted to 8.5 withtriethylamine and the mixture was allowed to stir at ambient temperaturefor 2 hours. Water was then added and the reaction mixture was extractedwith ethyl acetate. The combined organic extracts were washed with waterand brine, then dried (sodium sulfate) and concentrated to give thecrude product. This was purified by silica gel chromatography to afford120 mg (45%) of3,3,3-trifluoro-N-[(±)-trans-2-oxo-3-oxabicyclo[3.1.0]hex-1-yl]-propanamide.

3,3,3-Trifluoro-N-[(±)-trans-2-oxo-3-oxabicyclo[3.1.0]hex-1-yl]-propanamide(80 mg, 0.359 mmol) was dissolved in 700 μL of N,N-dimethyl-formamideunder an inert atmosphere. Methyl4′-(aminomethyl)-1,1′-biphenyl-2-carboxylate (95 mg, 0.395 mmol) wasadded and the mixture was heated to 60° C. After 10 hours the mixturewas concentrated to dryness. The residue was purified by silica gelchromatography (chloroform-methanol:94–6, v/v elution). This afforded 55mg (35%) of the title compound. Purity was determined by LCMS (ES MS,M+H⁺ found:465) and proton NMR (400 Mz, CDCl₃) δ 1.21–1.24 (dd, 1H),1.52–1.55 (dd, 1H), 1.6–1.7 (m, 2H), 3.05 (dd, 2H, CH ² CF₃), 3.43 (m,1H), 3.58 (br s, 1H, NH), 3.67 (s, 3H), 3.96–3.99 (dd, 1H), 4.48 (m, 2H,CH ² C₆H₄—), 7.26 (m, 4H), 7.34 (d, 1H), 7.41 (ddd, 1H), 7.47 (m, 1H,NH), 7.53 (ddd, 1H), 7.83 (dd, 1H).

EXAMPLE 5 Methyl3,3′-difluoro-4′-({[(1-{[methoxy(oxo)acetyl]amino}cyclopropyl)-carbonyl]amino}methyl)-1,1′-biphenyl-2-carboxylate

To a solution of methyl4′-({[(1-aminocyclopropyl)carbonyl]amino}-methyl)-3,3′-difluoro-;1,1′-biphenyl-2-carboxylate(0.25 g, 0.724 mmol, perpared according to the procedure described inExample 1) in methylene chloride 92 mL at 0° C. was added triethylamine(0.2 mL 1.44 mmol) followed by chloromethyl oxalate (0.07 mL, 0.76mmol). The reaction mixture was stirred at room temperature for 3 hoursand then poured into water and extracted with methylene chloride. Theorganics were dried over sodium sulfate, filtered, and then concentratedto obtain the crude product. This crude product was passed through asilica pad, eluting with 3:1 methylene chloride:EtOAc to afford thetitle compound as a glass. Purity was determined by LCMS (ES MS, M+₊Hfound:446) and proton NMR (400 MHz, CDCl₃: δ 7.71 (1H, s), 7.45(1H, dt,J=5.7 and 8.1 Hz), 7.35 (1H, t, J=7.8 Hz), 720–7.00 (4H, m), 6.79 (1H,m), 4.51(2H, d, J=6.0 Hz), 3.88(3H, s), 3.74(3H, s), 668(2H m), 1.11(2H, m) ppm.

EXAMPLE 6 Methyl4′-({[(1-{[amino(oxo)acetyl]amino}cyclopropyl)carbonyl]amino}methyl)-3,3′-difluoro-1,1′-biphenyl-2-carboxylate

To a solution of methyl3,3′-difluoro-4′-({[(1-{[methoxy(oxo)acetyl]-amino}cyclopropyl)carbonyl]amino}methyl)-1,1′-biphenyl-2-carboxylate(0.02 g, 0.045 mmol, Example 5) in methylene chloride (2 mL) at roomtemperature was added ammonia (0.224 mL of a 2M solution in methanol,0.45 mmol). The reaction mixture was stirred at room temperature for 4hrs and then concentrated to obtain the crude product. This crudeproduct was purified by reverse phase HPLC (Vydac column #218TP1022,gradient elution 5–95% acetonitrile:water containing 0.1% TFA). The purefractions were lyophilized to afford the title compound as a solid.Purity was determined by LCMS (ES MS, M+₊H found:432) and proton NMR(400 MHz, CDCl₃: δ 7.86 (1H,s), 7.45(1H,dt, J=5.7 and 8.1 Hz), 7.35 (1H,t, J=7.8 Hz), 7.20–7.00 (4H,m), 6.59 (1H, m), 5.61(1H, s), 4.54 (2H,d,J=6.0 Hz), 3.74(3H,s), 1.68(2H,m), 1.12 (2H,m) ppm.

The following compounds in Table 1 were prepared by methods analogous tothose described in Example 1.

TABLE 1

ES MS, Example R⁵ M + H⁺ 7 isoxazol-5-yl 420 8 cyanomethyl 392 91-hydroxypropyl 411 10 1-cyanocyclopropyl 418 113,5-bis(trifluoromethyl)phenyl 565 12 2,4-difluorophenyl 465 13 2-propyl395 14 4-methylphenyl 443 15 methoxymethyl 397 16 cyclopropyl 393 17thien-2-ylmethyl 449 18 3,4-dimethoxybenzyl 503 19 pyridin-3-yl 430 20pyridin-4-yl 430 21 1-benzothien-2-yl 485 22 3-methoxy-3-oxopropyl 43923 3,4-dimethoxyphenyl 489 24 benzyl 443 25 isobutyl 409 262-phenylethyl 457 27 cyclopentyl 421 28 4-cyanophenyl 454 293-nitrophenyl 474 30 1-ethylpropyl 423 31 2-phenylcyclopropyl 469 322-naphthyl 479 33 2-furyl 419 34 thien-2-yl 435 35 1,3-benzodioxol-5-yl473 36 (phenylthio)methyl 475 37 5-methylisoxazol-3-yl 434 38phenoxymethyl 459 39 2,2-dimethylpropyl 423 40 2-cyclopentylethyl 449 412-methoxy-2-oxoethyl 425 42 (1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-512 methyl 43 2-methoxyethyl 411 44 but-3-ynyl 405 45 ethoxymethyl 41146 tetrahydrofuran-3-yl 423 47 2-nitroethyl 426 484-methyl-1,2,5-oxadiazol-3-yl 435 49 3-cyanophenyl 454 50 2-cyanophenyl454 51 6-hydroxypyridin-2-yl 446 52 1-oxidopyridin-3-yl 446 536-choropyridin-2-yl 464 54 1-methyl-1H-pyrazol-4-yl 433 551H-pyrazol-1-ylmethyl 433 56 1-methyl-1H-imidazol-2-yl 433 571H-1,2,4-triazol-1-ylmethyl 434 58 thiazol-4-yl 436 595-oxotetrahydrofuran-2-yl 437 60 2-oxo-2H-pyran-5-yl 447 616-methylpyridin-2-yl 444 62 6-oxo-1,6-dihydropyridazin-3-yl 447 633,5-dimethylisoxazol-4-yl 448 64 1H-pyrazol-5-yl 419 65 isoxazol-3-yl420 66 oxazol-5-yl 420 67 pyridazin-3-yl 431 68 pyrimidin-5-yl 431 69pyrimidin-4-yl 431 70 1H-imidazol-1-ylmethyl 433 711-methyl-1H-pyrazol-5-yl 433 72 1-methyl-1H-pyrazol-3-yl 433 73thiazol-5-yl 436 74 (5-methyl-1H-pyrazol-1yl)methyl 447 75(3-methyl-1H-1,2,4-triazol-5-yl)methyl 448 762-(1H-1,2,4-triazol-1-yl)ethyl 448 77 5-methyl-thiazol-4-yl 450 78phenyl 429 79 3-fluorophenyl 447 80 3-methoxyphenyl 459 813-chlorophenyl 463 82 3,4-dichlorophenyl 497 833-(trifluoromethyl)phenyl 497 84 3-methylphenyl 443 85 quinoxalin-2-yl481 86 3,5-dichlorophenyl 497 87 2-chloropyridin-3-yl 464 883-hydroxyphenyl 445 89 3-nitro-5-(trifluoromethyl)phenyl 542 905-bromopyridin-3-yl 508 91 5-methyl-1-oxidopyridin-3-yl 459 925-hydroxypyridin-3-yl 446 93 5-bromo-1-oxidopyridin-3-yl 524 945-(methoxycarbonyl)pyridin-3-yl 488 95 tert-butyl 409 965-(carboxy)pyridin-3-yl 474 97 trifluoromethyl 421 983-(trifluoromethyl)pyridin-4-yl 498 99 5-(trifluoromethyl)pyridin-3-yl498

The following compounds in Table 2 were prepared by methods analogous tothose described in REFERENCE PROCEDURE 1.

TABLE 2

ES MS, Ex. R⁵ R^(6a) R^(6b) R^(6c) R^(7a) M + H⁺ 1002,2,2-trifluoroethyl CO₂Me F H F 471 101 Cyanomethyl CO₂Me F H F 428 102Isoxazol-5-yl CO₂Me F H F 456 103 2,2,2-trifluoroethyl trifluoromethyl FH F 481 104 Isoxazol-5-yl trifluoromethyl F H F 466 1052,2,2-trifluoroethyl (methylamino)sulfonyl H H F 488 106 Isoxazol-5-yl(methylamino)sulfonyl H H F 473 107 Pyrimidin-5-yl CO₂Me F H F 467 108Isoxazol-5-yl CO₂Me Cl H F 472 109 2,2,2-trifluoroethyl CO₂Me Cl H F 487110 Isoxazol-5-yl CO₂Me F F H 456 111 2,2,2-trifluoroethyl CO₂Me F F H471 112 2,2,2-trifluoroethyl CO₂Me F Me H 467 113 2,2,2-trifluoroethylCO₂Me Cl Me H 483 114 Isoxazol-5-yl CO₂Me F Me H 452 115 Isoxazol-5-ylCO₂Me Cl Me H 468 116 2,2,2-trifluoroethyl CO₂Me F H Cl 487 117Pyrimidin-5-yl CO₂Me F H Cl 483 118 2,2,2-trifluoroethyl CO₂Me F H H 453119 Pyrimidin-5-yl CO₂Me F H H 449 120 Isoxazol-5-yl CO₂Me F H Cl 472121 Isoxazol-5-yl 2-CH₃-2H-tetrazol-5-yl F H F 480 1222,2,2-trifluoroethyl 2-CH₃-2H-tetrazol-5-yl F H F 495 123 Pyrimidin-5-yl2-CH₃-2H-tetrazol-5-yl F H F 491 124 Pyrimidin-5-yl trifluoromethyl F HF 477 125 isoxazol-5-yl 3-CH₃-1,2,4-Oxadiazol-5-yl F H F 480 1262,2,2-trifluoroethyl 3-CH₃-1,2,4-oxadiazol-5-yl F H F 495 127pyrimidin-5-yl 3-CH₃-1,2,4-oxadiazol-5-yl F H F 491 1282,2,2-trifluoroethyl methoxy F H F 443 129 pyrimidin-5-yl methoxy F H F439 130 isoxazol-5-yl methoxy F H F 428 131 cyclopropyl CO₂Me F H Cl 445132 cyclopropyl CO₂Me F H H 411 133 pyrimidin-5-yl (methylamino)carbonylCl H F 482 134 pyrimidin-5-yl Cl Cl H F 459 135 pyrimidin-5-yl CO₂Me F HOCH₃ 479 136 trifluoromethyl CO₂Me F H F 457 137 dichloromethyl CO₂Me FH F 471 138 ethenyl CO₂Me F H F 415 139 (1E)-propenyl CO₂Me F H F 429140 propyl CO₂Me F H F 431 141 difluoromethyl CO₂Me F H F 439 142 methylCO₂Me F H F 403 143 pyrimidin-5-yl 1-methyl-ethyl H H F 433 144pyrimidin-5-yl CO₂Me F H OH 465 145 pyrimidin-5-yl CO₂H F H OH 451 146pyrimidin-5-yl H H H H 373 147 pyrimidin-5-yl CO₂Me F H NHCH₃ 478 148fur-3-yl CO₂Me F H H 437 149 (methylsulfonyl)- CO₂Me F H H 463 methyl150 trifluoromethyl trifluoromethyl F H F 467 151 1,1-dichloroethylCO₂Me F H F 485 152 trifluoromethyl 2-CH₃-2H-tetrazol-5yl F H F 481 153trifluoromethyl methoxy F H F 429 154 dichloromethyl2-CH₃-2H-tetrazol-5-yl F H F 495 155 5-(trifluoromethyl)- CO₂Me F H F534 pyridin-3-yl 156 trifluoromethyl 3-CH₃-1,2,4-oxadiazol-5-yl F H F481 157 1,1-dichloroethyl 3-CH₃-1,2,4-Ozadiazol-5-yl F H F 509 1582-carboxyethyl CO₂Me F H F 461 159 chlorodifluoro- CO₂Me F H F 473methyl 160 [(t-butoxycarbonyl)- CO₂Me F H F 518 amino]methyl 161aminomethyl CO₂Me F H F 418 162 5-bromopyridin-3-yl CO₂Me F H F 544 163pyrimidin-5-yl CO₂Me Cl H F 483 164 acetylaminomethyl CO₂Me F H F 460165 hydroxymethyl CO₂Me F H F 419 166 2-oxo-2-(pyridin-3- CO₂Me F H F508 yl)ethyl 167 trifluoromethyl CO₂Me Cl H F 473 168 phenyl CO₂Me F H F465 169 bromomethyl CO₂Me F H F 481 170 trifluoromethyl CO₂Me H F F 457171 pyrimidin-5-yl CO₂Me H F F 467 172 1-[(t-butoxy- CO₂Me F H F 532carbonyl)amino]- ethyl 173 (1R)-1-aminoethyl CO₂Me F H F 432 174(1R)-1-(acetyl- CO₂Me F H F 474 amino)ethyl 175 5-bromo-1-oxido- CO₂Me FH F 560 pyridin-3-yl 176 trifluoromethyl CO₂Me CH₃ H F 453 177pyrimidin-5-yl CO₂Me CH₃ H F 463 178 pyrimidin-5-yl CO₂Me F H SO₂CH₃ 527179 pyrimidin-5-yl Br H H F 469 180 pyrimidin-5-yl(methoxycarbonyl)amino F H F 482 181 pyrimidin-5-yl(ethoxycarbonyl)amino F H F 496 182 pyrimidin-5-yl(2-fluoroethoxycarbonyl)- F H F 514 amino 183 trifluoromethyl(methoxycarbonyl)amino F H F 472 184 1,1-difluoro-3- CO₂Me F H F 483hydroxypropyl 185 dimethylamino- CO₂Me F H F 446 methyl 1865-chloropyridin-3-yl CO₂Me F H F 500 187 5-fluoropyridin-3-yl CO₂Me F HF 484 188 pyrimidin-5-yl dimethylamino H H F 434 189 2-hydroxypyridin-3-CO₂Me F H F 482 yl 190 2-methoxypyridin- CO₂Me F H F 496 3-yl 1912-hydroxyphenyl CO₂Me F H F 481 192 trifluoromethyl[(methoxycarbonyl)amino] F H F 486 methyl 193 pyrimidin-5-yl[(methoxycarbonyl)amino] F H F 496 methyl 194 trifluoromethyl{[(methoxycarbonyl)amino] F H F 515 carbonyl}amino 195 pyrimidin-5-yl{[(methoxycarbonyl)amino] F H F 525 carbonyl}amino 196 2-oxopropyl CO₂MeF H F 445 197 2-methoxy-2-oxo- CO₂Me F H F 461 ethyl 198pentafluoroethyl CO₂Me F H F 507 199 trifluoromethyl(methylamino)carbonyl Cl H Cl 488 200 1-hydroxyethyl CO₂Me F H F 433 201trifluoromethyl (methylamino)carbonyl F H F 456 202 2-hydroxypropylCO₂Me F H F 447 203 1-(1-hydroxyethyl)- CO₂Me F H F 459 vinyl

The following compounds in Table 3 were prepared by methods analogous tothose described in REFERENCE PROCEDURE 2.

TABLE 3

ES MS, Example R⁵ R^(6a) M + H⁺ 204 isoxazol-5-yl (methoxyamino)carbonyl471 205 isoxazol-5-yl (dimethylamino)carbonyl 469 2062,2,2-trifluoroethyl (dimethylamino)carbonyl 484 207 isoxazol-5-yl(methylamino)carbonyl 455 208 2,2,2-trifluoroethyl (methylamino)carbonyl470 209 2,2,2-trifluoroethyl (methoxyamino)carbonyl 486 210pyrimidin-5-yl (cyclobutyloxy)carbonyl 507 211 pyrimidin-5-yl(isopropylamino)carbonyl 494 212 pyrimidin-5-yl (ethylamino)carbonyl 480213 pyrimidin-5-yl (isopropyloxy)carbonyl 495

The following compounds in Table 4 were prepared by elaboration of thecompound of Example 3 using procedures well known to those skilled inthe art.

TABLE 4

ES MS, Starting Example R^(4a)/R^(4b) Stereochemistry M + H⁺ materialReagent 214 hydroxymethyl, H (±)-cis 465 3 K₂CO₃/ MeOH 215 chloromethyl,H (±)-cis 483 217 SOCl₂ 216 CH₂ (±) 447 217 SOCl₂ 217[(methylsulfonyl)oxy]methyl, H (±)-cis 543 217 MsCl 218(methylthio)methyl, H (±)-cis 495 220 NaSMe 219 (dimethylamino)methyl, H(±)-cis 492 220 Me₂NH

The following compounds in Table 5 were prepared by methods analogous tothose described in REFERENCE PROCEDURE 1.

TABLE 5

ES MS, Example R⁵ M + H⁺ 220 pyrimidin-5-yl 485 221 trifluoromethyl 475

The following compounds in Table 6 were prepared by methods analogous tothose described in REFERENCE PROCEDURE 1.

TABLE 6

Exam- ES MS, ple R⁵ R^(6a) R^(6b) M + H⁺ 222 pyrimidin-5-yl formyl H 437223 pyrimidin-5-yl 1-hydroxyethyl H 453 224 trifluoromethyl3-methyl-1,2,4-Oxadiazol-5-yl H 481 225 pyrimidin-5-yl3-methyl-1,2,4-oxadiazol-5-yl H 491 226 trifluoromethyl CO₂Me H 457

The following compounds in Table 7 were prepared by methods analogous tothose described in Example 6.

TABLE 7

ES MS, Example R^(b) R^(c) M + H ⁺ 227 methyl H 446 228 methyl methyl460 229 2-(dimethylamino)ethyl H 503 230 2-(methylsulfonyl)ethyl H 538231 benzyl H 522 232 2-phenylethyl H 536

The following compounds in Table 8 were prepared by methods analogous tothose described in Example 1, using the commercially available1-[(tert-butoxycarbonyl)amino]cyclobutanecarboxylic acid instead of1-[(tert-butoxy-carbonyl)amino]cyclopropanecarboxylic acid.

TABLE 8

Example R⁵ R^(6b) R^(7a) ES MS, M + H⁺ 233 pyrimidin-5-yl H H 445 234pyrimidin-5-yl H F 463 235 pyrimidin-5-yl F F 481 236 CH₂CF₃ H H 449

1. A compound of formula I

wherein R¹ and R² are independently selected from (1) hydrogen and (2)C₁₋₄ alkyl; R^(4a) and R^(4b) are independently selected form (1)hydrogen, (2) halogen, and (3) C₁₋₄ alkyl optionally substituted with 1to 4 groups selected from halogen, OR^(a), OC(O)R^(a), S(O)_(k)R^(d),OS(O)₂R^(d), and NR¹R², or R^(4a) and R^(4b) together with the carbonatom to which they are both attached form an exo-cyclic methyleneoptionally substituted with 1 to 2 groups selected from C₁₋₄ alkyloptionally substituted with 1–5 halogens and C₁₋₄ alkyloxy; R⁵ isselected from (1) C₁₋₆ alkyl optionally substituted with 1 to 5 groupsindependently selected from halogen, nitro, cyano, OR^(a), SR^(a),COR^(a), SO₂R^(d), CO₂R^(a), OC(O)R^(a), NR^(b)R^(c), NR^(b)C(O)R^(a),NR^(b)C(O)₂R^(a), C(O)NR^(b)R^(c), C₃₋₈ cycloalkyl, (2) C₃₋₈ cycloalkyloptionally substituted with 1 to 5 groups independently selected fromhalogen, nitro, cyano and phenyl, (3) C₃₋₆ alkynyl, (4) C₂₋₆ alkenyloptionally substituted with hydroxyethyl, (5) (CH₂)_(k)-aryl optionallysubstituted with 1 to 3 groups independently selected from halogen,nitro, cyano, OR^(a), SR^(a), C(O)₂R^(a), C₁₋₄ alkyl and C₁₋₃ haloalkyl,wherein aryl is selected from phenyl, 3,4-methylenedioxyphenyl andnaphthyl; (6) (CH₂)_(k)-heterocycle optionally substituted with 1 to 3groups independently selected from halogen, nitro, cyano, OR^(a),SR^(a), C₁₋₄ alkyl and C₁₋₃ haloalkyl wherein said heterocycle isselected from (a) a 5-membered heteroaromatic ring having a ringheteroatom selected from N, O and S, and optionally having up to 3additional ring nitrogen atoms wherein said ring is optionallybenzo-fused; (b) a 6-membered heteroaromatic ring containing from 1 to 3ring nitrogen atoms and N-oxides thereof, wherein said ring isoptionally benzo-fused; and (c) a 5- or 6-membered non-aromaticheterocyclic ring selected from tetrahydrofuranyl,5-oxo-tetrahydrofuranyl, 2-oxo-2H-pyranyl, 6-oxo-1,6-dihydropyridazinyl,(7) C(O)₂R^(a), and (8) C(O)NR^(b)R^(c); R^(6a) is selected from (1)C₁₋₈ alkyl optionally substituted with 1–5 groups independently selectedfrom halogen, nitro, cyano, COR^(a), CO₂R^(a), C(O)NR^(b)R^(c), OR^(a),OC(O)R^(a), SR^(a), SO₂R^(d), S(O)R^(d), NR^(b)R^(c), NR^(b)C(O)R^(a),NR^(b)SO₂R^(d), NR^(b)CO₂R^(a), (2) C₃₋₈ cycloalkyl, (3) C₂₋₈ alkenyloptionally substituted with CO₂R^(a), (4) halogen, (5) cyano, (6) nitro,(7) NR^(b)R^(c), (8) NR^(b)C(O)R^(a), (9) NR^(b)CO₂R^(a), (10)NR^(b)C(O)NR^(b)R^(c), (11) NR^(b)C(O)NR^(b)CO₂R^(a), (12)NR^(b)SO₂R^(d), (13) CO₂R^(a), (14) COR^(a), (15) C(O)NR^(b)R^(c), (16)C(O)NHOR^(a), (17) C(═NOR^(a))R^(a), (18) C(═NOR^(a))NR^(b)R^(c), (19)OR^(a), (20) OC(O)R^(a), (21) S(O)_(k)R^(d), (22) SO₂NR^(b)R^(c), and(23) optionally substituted heterocycle where the heterocycle is a5-membered heteroaromatic ring having a ring heteroatom selected from N,O and S, and optionally having up to 3 additional ring nitrogen atoms,4,5-dihydro-oxazolyl and 4,5-dihydro-1,2,4-oxadiazolyl, and wherein saidsubstituent is 1 to 3 groups independently selected from C₁₋₄ alkyloptionally substituted with 1 to 5 halogen atoms, OR^(a) or OC(O)R^(a),R^(6b) and R^(6c) are independently selected from (1) hydrogen, and (2)a group from R^(6a); with the proviso that not more than one of R^(6a),R^(6b), and R^(6c) is a heterocycle; R^(7a) and R^(7b) are independentlyselected from (1) hydrogen, (2) halogen, (3) cyano, (4) nitro, (5)OR^(a), (6) CO₂R^(a), (7) C(O)NR^(b)R^(c). (8) C₁₋₄ alkyl optionallysubstituted with 1 to 5 halogen atoms, (9) NR^(b)R^(c), and (10)S(O)_(k)R^(d); R^(a) is selected from (1) hydrogen, (2) C₁₋₄ alkyloptionally substituted with 1 to 5 halogen atoms, (3) phenyl optionallysubstituted with 1 to 3 groups independently selected from halogen,cyano, nitro, OH, C₁₋₄ alkyloxy, C₃₋₆ cycloalkyl and C₁₋₄ alkyloptionally substituted with 1 to 5 halogen atoms, (4) C₃₋₆ cycloalkyl,and (5) pyridyl optionally substituted with 1 to 3 groups independentlyselected from halogen and C₁₋₄ alkyl; R^(b) and R^(c) are independentlyselected from (1) hydrogen, (2) C₁₋₄ alkyl optionally substituted with 1to 5 groups independently selected from halogen, amino,mono-C₁₋₄alkylamino, di-C₁₋₄alkylamino, and SO₂R^(d), (3)(CH₂)_(k)-phenyl optionally substituted with 1 to 3 groups selected fromhalogen, cyano, nitro, OH, C₁₋₄ alkyloxy, C₃₋₆ cycloalkyl and C₁₋₄ alkyloptionally substituted with 1 to 5 halogen atoms, and (4) C₃₋₆cycloalkyl, or R^(b) and R^(c) together with the nitrogen atom to whichthey are attached form a 4-, 5-, or 6-membered ring optionallycontaining an additional heteroatom selected from N, O, and S; or R^(b)and R^(c) together with the nitrogen atom to which they are attachedform a cyclic imide; R^(d) is selected from (1) C₁₋₄ alkyl optionallysubstituted with 1 to 5 halogen atoms, (2) C₁₋₄ alkyloxy, and (3) phenyloptionally substituted with 1 to 3 groups selected from halogen, cyano,nitro, OH, C₁₋₄ alkyloxy, C₃₋₆ cycloalkyl and C₁₋₄ alkyl optionallysubstituted with 1 to 5 halogen atoms; k is 0, 1 or 2; and m is 0 or 1.2. A compound of claim 1 wherein R¹ and R² are each hydrogen.
 3. Acompound of claim 1 wherein one of R^(4a) and R^(4b) is hydrogen and theother is selected from hydrogen, halogen and C₁₋₄ alkyl optionallysubstituted with a group selected from halogen, OR^(a), OC(O)R^(a),S(O)_(k)R^(d), OS(O)₂R^(d) and NR¹R², or R^(4a) and R^(4b) together withthe carbon atom to which they are both attached form an exo-cyclicmethylene.
 4. A compound of claim 1 wherein R^(4a) and R^(4b) are eachhydrogen.
 5. A compound of claim 1 wherein R^(4a) is hydrogen and R^(4b)is selected from CH₂-halogen, CH₂—OR^(a), CH₂—OC(O)R^(a),CH₂—S(O)_(k)R^(d), CH₂—OS(O)₂R^(d), and CH₂—NR¹R².
 6. A compound ofclaim 1 wherein R⁵ is C₁₋₆ alkyl optionally substituted with 1 to 5groups independently selected from halogen, nitro, cyano, OR^(a),SR^(a), COR^(a), SO₂R^(d), CO₂R^(a), OC(O)R^(a), NR^(b)R^(c),NR^(b)C(O)R^(a), C(O)NR^(b)R^(c)C₃₋₈ cycloalkyl.
 7. A compound of claim1 wherein R⁵ is selected from C₁₋₅ alkyl and C₁₋₃ alkyl substituted with1 to 3 groups selected from halogen, cyano, hydroxy, C₁₋₄ alkoxy andC₁₋₄ alkoxycarbonyl.
 8. A compound of claim 1 wherein R⁵ is selectedfrom C₁₋₃ alkyl substituted with 1 to 3 groups selected from chloro,fluoro and cyano.
 9. A compound of claim 1 wherein R⁵ is C₃₋₆ cycloalkyloptionally substituted with 1 to 3 groups independently selected fromhalogen, nitro, cyano and phenyl.
 10. A compound of claim 1 wherein R⁵is (CH₂)_(k)-aryl optionally substituted with 1 to 3 groupsindependently selected from halogen, nitro, cyano, OR^(a), SR^(a), C₁₋₄alkyl and C₁₋₃ haloalkyl, wherein aryl is selected from phenyl,3,4-methylenedioxyphenyl and naphthyl.
 11. A compound of claim 1 whereinR⁵ is phenyl optionally substituted with 1 to 2 groups selected frommethyl, trifluoromethyl, halogen, cyano, nitro and methoxy.
 12. Acompound of claim 1 wherein (CH₂)_(k)-heterocycle optionally substitutedwith 1 to 3 groups independently selected from halogen, nitro, cyano,OR^(a), SR^(a), C₁₋₄ alkyl and C₁₋₃ haloalkyl wherein said heterocycleis selected from (a) a 5-membered heteroaromatic ring having a ringheteroatom selected from N, O and S, and optionally having up to 3additional ring nitrogen atoms wherein said ring is optionallybenzo-fused; and (b) a 6-membered heteroaromatic ring containing from 1to 3 ring nitrogen atoms wherein said ring is optionally benzo-fused.13. A compound of claim 1 wherein R⁵ is (CH₂)_(k)-heterocycle optionallysubstituted with 1 to 2 groups independently selected from halogen,nitro, cyano, OR^(a), SR^(a), C₁₋₄ alkyl and C₁₋₃ haloalkyl wherein saidheterocycle is selected from isoxazolyl, thienyl, pyridinyl,benzothienyl, furyl, oxadiazolyl, 1-oxidopyridinyl, pyrazolyl,imidazolyl, 1,2,4-triazolyl, thiazolyl, 5-oxotetrahydrofuranyl,2-oxo-2H-pyranyl, 6-oxo-1,6-dihydropyridazinyl, oxazolyl, pyridazinyl,pyrimidinyl and quinoxalinyl.
 14. A compound of claim 1 wherein R⁵ isselected from isoxazolyl optionally substituted with 1 or 2 C₁₋₄ alkyl,thienyl, pyridinyl optionally substituted with hydroxy or halogen,benzothienyl, furyl, tetrahydrofuranyl, oxadiazolyl optionallysubstituted with C₁₋₄ alkyl, 1-oxidopyridinyl optionally substitutedwith C₁₋₄ alkyl, pyrazolyl optionally substituted with C₁₋₄ alkyl,imidazolyl optionally substituted with C₁₋₄ alkyl, 1,2,4-triazolyloptionally substituted with C₁₋₄ alkyl, thiazolyl optionally substitutedwith C₁₋₄ alkyl, 5-oxotetrahydrofuranyl, 2-oxo-2H-pyranyl,6-oxo-1,6-dihydropyridazinyl, oxazolyl, pyridazinyl, pyrimidinyl andquinoxalinyl.
 15. A compound of claim 1 wherein R⁵ is selected fromisoxazolyl optionally substituted with C₁₋₄ alkyl, pyrimidinyl,pyridinyl optionally substituted with halogen or C₁₋₄ alkyl and N-oxidesthereof.
 16. A compound of claim 1 wherein R⁵ is selected from C₁₋₃alkyl substituted with 1 to 3 halogen atoms, 5-isoxazole and5-pyrimidinyl.
 17. A compound of claim 1 having the formula I(1):

wherein m, R¹, R^(4a), R^(4b), R⁵, R^(6a), R^(6b), R^(6c) and R^(7a) areas defined in claim
 1. 18. A compound of claim 17 wherein R^(6a) isselected from (1) CO₂R^(a), (2) C(O)NHOR^(a), (3) cyano, (4) halogen,(5) OR^(a), (6) C₁₋₈ alkyl optionally substituted with 1–5 halogenatoms, or a group selected from CO₂R^(a), C(O)NR^(b)R^(c) and OR^(a),(7) C(O)NR^(b)R^(c), (8) NR^(b)C(O)NR^(b)R^(c), (9) NR^(b)C(O)OR^(a),and (10) optionally substituted heterocycle where the heterocycle isselected from oxadiazolyl and tetrazolyl and wherein said substituent is1 to 3 groups independently selected from C₁₋₄ alkyl optionallysubstituted with 1 to 5 halogen atoms, OR^(a) or OC(O)R^(a).
 19. Acompound of claim 17 wherein R^(6a) is selected from CO₂R^(a),C(O)NHOR^(a), methyltetrazolyl, methyloxadiazolyl,NR^(b)C(O)NR^(b)R^(c), and NR^(b)C(O)OR^(a).
 20. A compound of claim 17wherein R^(6b) is selected from hydrogen, halogen and CO₂R^(a).
 21. Acompound of claim 17 wherein R^(6b) is hydrogen, chloro or fluoro.
 22. Acompound of claim 17 wherein R⁵ is selected from C₁₋₄ alkyl optionallysubstituted with 1 to 5 halogen atoms or a cyano group, C₃₋₆ cycloalkyl,isoxazolyl, pyrimidinyl and pyridinyl (and N-oxide thereof) optionallysubstituted with halogen.
 23. A compound of claim 1 having the formulaI(2):

wherein m, R⁵, R^(6a), R^(6b) and R^(7a) are as defined in claim
 1. 24.A compound of claim 23 wherein R^(6b) is hydrogen or halogen.
 25. Acompound of claim 23 wherein R^(6b) is hydrogen.
 26. A compound of claim23 wherein R^(6b) is fluorine or chlorine.
 27. A compound of claim 23wherein R^(6a) is selected from (1) CO₂R^(a), (2) C(O)NHOR^(a), (3)cyano, (4) halogen, (5) OR^(a), (6) C₁₋₈ alkyl optionally substitutedwith 1–5 halogen atoms, or a group selected from CO₂R^(a),C(O)NR^(b)R^(c) and OR^(a), (7) C(O)NR^(b)R^(c), (8)NR^(b)C(O)NR^(b)R^(c), (9) NR^(b)C(O)OR^(a), and (10) optionallysubstituted heterocycle where the heterocycle is selected fromoxadiazolyl and tetrazolyl and wherein said substituent is 1 to 3 groupsindependently selected from C₁₋₄ alkyl optionally substituted with 1 to5 halogen atoms, OR^(a) or OC(O)R^(a).
 28. A compound of claim 23wherein R^(6a) is selected from CO₂R^(a), C(O)NHOR^(a),methyltetrazolyl, methyloxadiazolyl, NR^(b)C(O)NR^(b)R^(c), andNR^(b)C(O)OR^(a).
 29. A compound of claim 23 wherein R^(6a) is selectedfrom CO₂R^(a), methyltetrazolyl and methyloxadiazolyl.
 30. A compound ofclaim 23 wherein in another embodiment R^(7a) is hydrogen or halogen.31. A compound of claim 23 wherein R^(7a) is hydrogen.
 32. A compound ofclaim 23 wherein R^(7a) is fluorine.
 33. A compound of claim 23 whereinR⁵ is selected from C₁₋₄ alkyl optionally substituted with 1 to 5halogen atoms or a cyano group, C₃₋₆ cycloalkyl, isoxazolyl, pyrimidinyland pyridinyl (and N-oxide thereof) optionally substituted with halogen.34. A compound of claim 23 wherein m is 0 or 1, R^(6a) is2-methyl-2H-tetrazol-5-yl, 3-methyl-1,2,4-oxadiazol-5-yl, CO₂R^(a) orC(O)NHOR^(a) wherein R^(a) is C₁₋₄ alkyl; R^(6b) is hydrogen, fluorineor chlorine; R⁵ is selected from C₁₋₄ alkyl optionally substituted with1 to 5 halogen atoms or a cyano group, C₃₋₆ cycloalkyl, isoxazolyl,pyrimidinyl and pyridinyl (and N-oxide thereof) optionally substitutedwith halogen or trifluoromethyl; and R^(7a) is hydrogen or fluorine. 35.A pharmaceutical composition comprising a therapeutically effectiveamount of a compound of claim 1 and pharmaceutically acceptableexcipients.